Regulation of monocyte differentiation by specific signaling modules and associated transcription factor networks (original) (raw)

Abstract

Monocyte/macrophages are important players in orchestrating the immune response as well as connecting innate and adaptive immunity. Myelopoiesis and monopoiesis are characterized by the interplay between expansion of stem/progenitor cells and progression towards further developed (myelo)monocytic phenotypes. In response to a variety of differentiation-inducing stimuli, various prominent signaling pathways are activated. Subsequently, specific transcription factors are induced, regulating cell proliferation and maturation. This review article focuses on the integration of signaling modules and transcriptional networks involved in the determination of monocytic differentiation.

Keywords: Monocytes, Macrophages, Signaling, Transcription, Differentiation

Monocytic differentiation and function

Monocytes are bone marrow-derived mononuclear cells giving rise to macrophages and dendritic cells (DC) [1]. Together, these leukocytes are part of the cellular arm of the innate immune system representing the mononuclear phagocyte system [1, 2]. In addition, cells of the monocytic lineage support the activation of the adaptive immune system by antigen presentation, thus linking innate and adaptive immunity.

Hematopoietic stem cells (HSC)

The monocytic development, which comprises several myeloid and premonocytic stages, is initiated in the bone marrow by multipotent, self-renewing HSC (Fig. 1). The stem cell status of HSC is maintained in response to a variety of extracellular signals (e.g., angiopoietin, thrombopoietin, stem cell factor (SCF), and CXCL12) [3] regulating a network of transcription factors that suppress the initiation of cellular differentiation and lineage commitment [4]. In particular, transcriptional regulators such as Gfi1, Bmi1, signal transducer and activator of transcription (STAT) 5, and Homeobox family members (e.g., Hox B4, A4, A9, and B6) have been identified to be decisively involved in bone marrow homing, maintenance of the undifferentiated cell status, cell cycle regulation, and HSC expansion [5–7]. In the course of maturation, the composition of the relevant transcription factor network changes in response to differentiation-supporting stimuli, thus effectively modifying the overarching transcription factor architecture within the cells, which is discussed later. To provide both the maintenance of their multipotent/self-renewal potential and the formation of initially differentiated, lineage-committing progenies, HSC are able to undergo asymmetrical cell divisions, resulting in the formation of two deviating daughter cells [8]. Thus, the number of HSC in the stem cell pool is preserved [6] and the development of a series of myeloid and lymphoid progenitors without self-renewal potential, but characterized by (decreasing) proliferative and (increasing) differentiating capacity, is enabled [9]. In consequence, asymmetrical division of HSC and their progenies provides the cellular basis for the creation and maintenance of the whole hematopoietic system [3]. Although the mechanisms regulating hematopoietic homeostasis at the stem cell level are not fully understood, it is generally accepted that these processes are regulated by environmental signals in the bone marrow stem cell niche [3, 8]. Dependent on the particular conditions to which a single HSC is exposed, the cell may take different cell fates, including asymmetrical division and the release of early progenitor cells to external micro-environments for further maturation [3, 10]. To date, the molecular basis for a cell-intrinsic polarity of HSC is still unclear. However, it has been reported that unbalanced levels of Notch signaling, which is involved in the regulation of cell fate decisions during developmental processes, are present in the daughter cells of asymmetrically dividing HSC, presumably induced by segregation of Numb, a regulator of Notch signaling [8].

Fig. 1.

The development of monocytic cells. The scheme shows the different myeloid and premonocytic stages of monocytic maturation beginning with self-renewing HSC in the bone marrow via several myeloid progenitors resulting in the formation of blood monocytes. Further developmental steps yield the generation of macrophages and DC in different tissues. Further details are described in the text (HSC hematopoietic stem cell, MPP multipotent progenitor, CMP common myeloid progenitor, GMP granulocyte/monocyte progenitor, MDP monocyte/macrophage and dendritic cell progenitor, MΦ macrophage)

Progenitor stages

The first, but still non-specific developmental step towards monocytes, is represented by multipotent progenitors (MPP), common progenitors of all myeloid and lymphoid cells, which have lost the stem cell-specific self-renewal capacity [9]. Then, common myeloid progenitors (CMP) are formed, which give rise to all myeloid cells, followed by the granulocyte/monocyte progenitor (GMP) as the source of both granulocytes as well as the monocytic lineage [9]. Further differentiation of GMP creates the monocyte/macrophage and dendritic cell progenitor (MDP), which has lost the ability to generate granulocytes but provides the basis for monocytic lineage development, including monoblasts, promonocytes, monocytes, macrophages, and DC [1]. The complex network of differentiating progenitors illustrates the differentiation plasticity of hematopoietic cells and reflects their ability to undergo lineage switches even in more differentiated developmental stages [11]. Due to the imperative of producing large amounts of mature cells from a limited number of progenitors, monopoiesis occurs within the interplay of proliferation and differentiation. While early myeloid progenitor cells exhibit a significant proliferative potential even during differentiation [1], later stages are characterized by increasingly limited duplication and a deceleration or arrest of the cell cycle, thus indicating progressing terminal differentiation [12].

Blood monocytes

Mature monocytes translocate to the bloodstream where they patrol for a few days on the endothelial cell layer in a transient inactive state [1, 13], screening for indication of infections or cell damage [14]. Subsequently, they extravasate or undergo apoptosis. Three subsets of human blood monocytes have been identified to date: classical CD14++CD16− monocytes, intermediate CD14++CD16+ monocytes, and non-classical CD14+CD16++ monocytes [15]. The emigration from the bloodstream into adjacent tissues includes processes like capture, rolling, arrest, adhesion, crawling, and transendothelial migration [14].

Macrophages and DC

Tissue-directed monocytes may physiologically differentiate into resident macrophages and DC, thus contributing especially to tissue homeostasis (Fig. 1) [1]. Prominent representatives of tissue-specific macrophages are alveolar macrophages (lung), Kupffer cells (liver), subcapsular sinusoidal and medullary macrophages (lymph nodes), white-pulp and metallophilic macrophages (spleen), intestinal macrophages (small intestine), intraocular macrophages (eye), and microglia (central nervous system) [1, 13, 16, 17]. Similarly, DC may stably reside in several organs and tissues, e.g., epidermis (Langerhans cells), intestine, respiratory mucosa, spleen, and bone marrow [18]. During the process of differentiation, monocytes and their further-developed descendants gain and diversify their distinct molecular, morphological, and functional properties [2, 19, 20]. This also includes the formation of a characteristic macrophage- or DC-like phenotype by cytoskeletal rearrangements [21], modulation of nuclear architecture [22], and changes in the cellular distribution of adhesion molecules [23].

Morphological changes

During monopoiesis, the progenitor stages are characterized by the formation of round, non-adherent cells containing large nuclei and low amounts of cytoplasm. In contrast to the morphologically unobtrusive, relatively small stem and early progenitor cells containing generally round nuclei [24, 25], the monoblasts, promonocytes, and monocytes represent larger cell types with increasingly indented nuclei [26, 27]. Further developmental steps yield the generation of clearly shaped macrophages and DC [28]. Macrophages are adherent cells with a flattened, spindle-shaped, amoeboid, and/or polygonal morphology [21] and a large, indented nucleus, also possessing an increased cytoplasmatic volume and—especially following activation—an enhanced number of mitochondria, Golgi apparatus components, lipid droplets, and acid phosphatase-positive granules [29, 30]. DC also represent an adherent cell type characterized by a flattened, granular body, a large nucleus, and stellate/dendritical cytoplasmic extensions [28].

Immunological functions and pathophysiological aspects

Especially in exposed tissues such as the intestinal lumen and the bronchoalveolar space, which are important gateways for infections, monocyte/macrophage populations adopt important functions in surveillance and primary host defense [31]. In response to chemokines and other granule proteins which may be produced by polymorphonuclear leukocytes following tissue injury or infections, monocytes may also invade inflamed or damaged tissue [32]. Under these conditions, monocytic cells contribute to host defense by mediating early proinflammatory and antimicrobial events [31] as well as clearing of apoptotic cells, cell debris, and toxic molecules [13]. Subsequently, these monocytes may further differentiate within hours into inflammatory macrophages and DC [1, 13], which amplify the local immune response by cytokine/chemokine production, phagocytosis as well as antigen presentation [13, 33]. In addition, the formation of alternatively activated macrophages is possible, which are involved in tissue remodeling, wound repair, and immunomodulation [1]. Hyperactivated and dysregulated as well as degenerated or transformed monocyte-derived cells may be involved in numerous diseases, e.g., sepsis [34], chronic inflammatory diseases such as rheumatoid arthritis and atherosclerosis [35–38], obesity [39], leukemia [9] as well as persistence of bacterial and viral infections such as tuberculosis or HIV-1 [31, 40].

Focus of the review

Pathophysiological mechanisms underlying infections, inflammation, leukemia, and hyperproliferation have been extensively reviewed elsewhere [31, 34, 41]. This review focuses on the integration of signaling modules and transcriptional networks involved in physiological aspects of progenitor cell expansion and myelomonocytic differentiation, and aspects of monocyte function are mentioned throughout the text.

Differentiation-associated signaling modules

Monocytic differentiation initially depends on the interaction of differentiation-inducing stimuli with their cognate receptors [42]. Subsequently, distinct signaling pathways are induced, resulting in the expression and activation of the variety of differentiation-associated transcription factors [42, 43]. In the following, the most important stimuli are specified. Afterwards, the respective signal transduction pathways are described in detail and summarized in Fig. 2.

Fig. 2.

Signaling modules and associated transcription factor networks contributing to monocytic differentiation. A simplified flow diagram is shown summarizing the most important signaling modules involved in monopoiesis by orchestrating progenitor cell expansion and maturation of (myelo)monocytic cells. Furthermore, the most important connections between signaling cascades and transcriptional networks are depicted. Potential key molecules and the most prominent associations are indicated in red. Beyond regulation of transcriptional networks, several signaling molecules may also directly influence additional regulatory levels and cellular functions during monocyte/macrophage differentiation, which are not shown in this figure (for further details, see text)

Differentiation-inducing stimuli

In cells of the myelomonocytic lineage, differentiation is induced in response to a variety of different stimuli.

Fms-like tyrosine kinase 3 ligand (FLT3L)

During myelo- and monopoiesis, especially during the initial steps, FLT3L represents an important stimulus sustaining cell survival and driving the expansion of hematopoietic progenitors [44]. FLT3L binds to the Fms-like tyrosine kinase 3 receptor (FLT3) and may activate several signaling pathways. FLT3L may also support (pre)monocytic differentiation under certain conditions [44]. Its key feature, however, remains the maintenance and expansion of immature progenitor cells.

Colony-stimulating factors (CSF)

CSF exhibit both pro-proliferative and differentiation-inducing qualities (for a detailed review, see [45]). The CSF family consists of granulocyte/macrophage CSF (GM-CSF), macrophage CSF (M-CSF), granulocyte CSF (G-CSF), and interleukin (IL)-3 (also denoted multi-CSF). Like FLT3L, GM-CSF and IL-3 are crucial factors affecting survival and expansion of early hematopoietic progenitors [45]. In addition, they are able to induce initial steps of progenitor cell maturation. M-CSF and G-CSF are important inducers of monocyte and granulocyte development, respectively [45]. They are involved in regulating survival and proliferation of monocyte/granulocyte precursors and their maturation towards monocyte/macrophages or neutrophil granulocytes, thus also driving lineage commitment decisions [46]. A combined treatment with IL-3 and M-CSF, for example, efficiently differentiates embryonic stem cell lines (KCL001, KCL002, and HUES-2) towards homogenous monocytic cells [47].

Deltanoids

Deltanoids, i.e., vitamin D3 (VitD3), its biologically active form 1,25-dihydroxy vitamin D3 (1,25(OH)2D3), and other derivatives and analogues are prominent physiological agents inducing monocytic differentiation [48, 49]. 1,25(OH)2D3-induced gene expression contributes to the inhibition of proliferation, differentiation of cells of the monocytic lineage, and modulation of differentiation-related functions, e.g., the immune response [49, 50]. The effect of 1,25(OH)2D3 may be antagonized by lipopolysaccharide (LPS), a repressor of vitamin D receptor (VDR) expression [51].

Retinoids

Retinoids such as retinoic acid (RA) or all-trans retinoic acid (ATRA) also have been described as inducers of myeloid differentiation [43]. Stimulation of human (pre)monocytic cell lines such as THP-1 and HL-60 with RA or ATRA has been shown to provoke inhibition of proliferation [52, 53] and the expression of maturation-associated genes (e.g., peroxisome proliferator activated receptor γ1) [54]. Moreover, differentiation of THP-1 towards a macrophage-like phenotype can be induced with high concentrations of RA and ATRA [55, 56]. In the presence of additional agents such as bile acids or catalase, lower retinoid concentrations may also contribute to the differentiation of THP-1 and HL-60 cells [57, 58]. In addition, retinoids are able to enhance the differentiation-inducing effect of 1,25(OH)2D3 as demonstrated in U937 cells [59]. However, within the myeloid lineage, retinoids appear to predominantly induce the formation of granulocytes [43] as shown for HL-60 cells, normal or chronic myelogenous leukemia (CML)-derived GMP, and myelodysplastic syndrome-derived primary human bone marrow cells [60–62].

Cytokines and other growth factors

IL-1β stimulation yields the differentiation of murine WEHI-3B JCS myelomonocytic leukemia cells towards macrophage-like cells [63]. Growth inhibition and monocyte/macrophage differentiation was also induced by tumor necrosis factor (TNF) in ML-1 human myelogenous leukemia cells [64] and WEHI-3B JCS cells [65], an effect which is further enhanced in the presence of IL-1α, IL-1β [63], and IL-4 [66]. Stimulation of primary human monocytes with IL-4 or IL-15 results in the development of macrophages [67]. In murine M1 myeloid leukemia cells, monocyte/macrophage formation has been demonstrated to be induced by IL-6, leukemic inhibitory factor, and oncostatin M (OSM) [68]. IL-32 treatment of primary human monocytes and THP-1 cells induces monocyte/macrophage differentiation and reversed GM-CSF/IL-4-induced DC development resulting in the formation of macrophages [69]. Other factors supporting myelomonocytic differentiation and restricting the proliferation of hematopoietic cells, are members of the transforming growth factor (TGF)-β [42] and interferon (IFN) families [70]. TGF-β restricts proliferation of stem and progenitor cells by cell cycle inhibition and enhances monocytic/granulocytic differentiation [42]. IFN-γ influences myelomonocytic differentiation, lineage commitment decisions, and development of monocyte/macrophage functions [70, 71].

Microbial products

An infection of primary human HSC with Listeria monocytogenes or Yersinia enterocolitica predominantly induced the expression of monocyte differentiation markers [72]. In guinea pigs, the injection of killed Mycobacterium tuberculosis results in monocyte/macrophage differentiation in vivo [73]. The _Mycoplasma fermentans_-derived protein P48 is able to induce growth arrest and monocytic differentiation of M1, HL-60, and U937 cells [74]. Furthermore, HIV-1 infection also induces monocytic differentiation of U937 and human myelomonoblastic PLB-985 cells [75, 76].

Further agents

Monocytic differentiation can also be effectively initiated using phorbol esters such as phorbol-12-myristate 13-acetate (PMA) [77]. PMA-induced delay/inhibition of proliferation [78] and differentiation towards monocyte/macrophages have been demonstrated in a variety of leukemia-derived cell lines such as HL-60, U937, and THP-1 [79–81]. Monocytic maturation may be induced or supported by a variety of further substances. For instance, in several leukemia cell lines, an inhibition of proliferation and/or the differentiation towards a monocytic phenotype can be provoked by vitamin E (VitE)-succinate [82], adhesion molecules (e.g., laminin, fibronectin) [82, 83], and triterpenoids such as ursolic acid (UA) [84] or 2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid (CDDO) [85].

Fms-like tyrosine kinase 3 (FLT3) pathway

The FLT3 receptor system is a major contributor to proliferation and expansion of hematopoietic stem and progenitor cells in response to FLT3L [44]. FLT3 is a member of the receptor tyrosine kinase class III family predominantly expressed on hematopoietic stem and progenitor cells, but also premonocytic cells [86]. Moreover, FLT3 has been suggested to play an important role in the pathogenesis of acute myeloid leukemia (AML) [44]. FLT3 directly activates several signal cascades, e.g., mitogen-activated protein kinase (MAPK)- and phosphoinositide-3-kinase (PI3K)-involving pathways (see below) [44].

FLT3-dependent effects in myelomonocytic cells

FLT3 is expressed in primitive hematopoietic progenitor cells and its expression is increased and maintained during (pre)monocytic differentiation [87]. Following activation, FLT3 promotes proliferation of early hematopoietic progenitor cells [88]. Thus, the amount of available progenitors, especially GMP, is expanded [88, 89]. In the absence of further pro-proliferative agents, FLT3 appears to support differentiation of early hematopoietic progenitors towards a monocytic phenotype [88, 89]. Treatment of HSC with FLT3L, thrombopoietin, and SCF has also been demonstrated to result in monocytic differentiation [90]. Interestingly, FLT3 deficiency seems not to affect myelomonocytic development severely as shown by virtually normal hematopoiesis in FLT3ko mice [91]. However, in irradiated mice, a combined transplantation of two hematopoietic progenitor cell populations expressing either an inactive FLT3 variant or the FLT3wt receptor reveals a predominant reconstitution of the bone marrow by FLT3wt-positive cells [91], indicating the positive (but at least not essential) influence of FLT3 on hematopoietic cell proliferation/replenishment [44]. FLT3 presumably supports proliferation of hematopoietic/myelomonocytic cells by inducing C/EBPβ-liver-enriched inhibitory protein (LIP) and decreasing the liver-enriched activating protein (LAP)/LIP ratio [92]. Moreover, an increased expression of C/EBPα and purine-rich box 1 (PU.1) has been described in FLT3L-stimulated FLT3wt cells [93].

Phosphoinositide-3-kinase (PI3K) pathway

PI3K-dependent signaling is initiated in response to ligand-induced receptor activation by cytokines and growth factors [94] and renders significant contributions to hematopoietic cell survival [42]. The PI3K family consists of three subfamilies (class I-III) of which class I has been shown to contribute to the regulation of hematopoiesis [95]. Class I includes G protein-coupled receptor (GPCR)- and receptor tyrosine kinase (RTK)-activated class IA PI3K with a regulatory subunit (p85α or β, p50α, p55α or γ) and a catalytic subunit (p110α, β, or δ) as well as selectively GPCR-activated class IB PI3K (regulatory subunit: p101, catalytic subunit p110γ). Following activation and recruitment to the cell membrane, class I PI3K are able to phosphorylate membrane-bound phosphoinositide-4,5-bisphosphate resulting in the formation of phosphoinositide-3,4,5-trisphosphate (PIP3) [95]. PIP3 may serve as an anchor molecule for the pleckstrin homology domain of protein kinase B (PKB) (isoforms: α, β, γ) thus recruiting PKB to the cell membrane. Following activation, PKB is able to translocate to the cytoplasm and to phosphorylate its substrates.

PI3K-dependent effects

PI3K/PKB activation has been demonstrated during 1,25(OH)2D3-induced monocytic differentiation of HL-60 cells [96] and sRAGE-induced monocyte-to-macrophage differentiation [97]. PI3K has also been shown to be involved in monocytic actin reorganization and adhesion [98, 99].

PKB-dependent transcription factors

Downstream, a variety of PKB substrates may be negatively regulated including glycogen synthase kinase 3 (GSK3), FoxO1/3/4, and TSC1/2 [95]. PI3K/PKB may support proliferation, survival, and differentiation of myelomonocytic progenitors since it has been suggested that GSK3 is involved in maintaining HSC and restricting neutrophil development, at least in part via negatively regulating C/EBPα [95]. In addition, inactivation of GSK3 leads to the induction of β-catenin as shown in K562 CML cells [100]. FoxO proteins negatively regulate both HSC proliferation/expansion and myeloid lineage commitment [95]. PKB also supports activation of Rheb, a mammalian target of rapamycin (mTOR)-activating Ras family GTPase, by inhibiting TSC1/2, which is a negative regulator of Rheb. Consequently, PKB positively influences mTOR activity [101]. Subsequently, activated mTOR appears to enhance HSC and progenitor cell proliferation [95] presumably by upregulating pro-proliferative C/EBPα-p30 and C/EBPβ-LIP [102, 103]. It has also been shown that M-CSF-induced and spliceosome complex protein THOC5-mediated increase in C/EBPα, C/EBPβ, and PU.1 expression also involves PIP3 [104], suggesting a role of PI3K/PKB signaling within this context. Moreover, PKB appears to be involved in distinct lineage commitment decision, since it has been shown that transduction of constitutively active PKB induces neutrophil and monocyte formation [42].

Mitogen-activated protein kinase (MAPK) pathway

MAPK signaling is a crucial mechanism controlling fundamental processes such as growth, proliferation, survival, motility, and migration and involves numerous variations of participating signaling mediators such as cytokines, growth factors, and PMA [105, 106]. In addition, differentiation and hematopoiesis may also be regulated by MAPK pathways, especially involving extracellular signal-regulated kinase (ERK) 1/2, and/or c-Jun N-terminal kinase (JNK) [107].

Ras, Raf, MAPK/ERK kinase (MEK), and ERK

The mammalian Ras family of small GTPases comprises a variety of proteins (H-, K-, N-, E-, R-, M-Ras, TC21, RalA/B, Rap1A/B, Rap2A/B/C, Rit1/2, Rheb/L1) acting as activators of Raf family kinases [108]. An activation of Ras-dependent signaling results in the increased expression and activation of activator protein (AP)-1 transcription factors, e.g., c-Jun, JunB, and Fos-related antigen (Fra)-1/2. In general, Ras proteins are strongly involved in regulating proliferation or tumorigenesis/malignancy [109] and Ras signaling-associated antiproliferative capacity is an important feature by which Ras contributes to monocytic differentiation. Ras has been shown to negatively regulate cell cycle progression in several cell types by inducing the expression and/or activation of cell cycle inhibitors such as p15, p16 [110], p19 [111], p21, and p53 [112]. In U937 and K562 cells transduced with constitutively active N-Ras, Ras-dependent antiproliferative effects appear to be mediated via interferon regulatory factor (IRF)-1 [113]. Consequently, Ras-mediated growth arrest may render myeloid cells susceptible to differentiation-promoting agents [42]. The level of active Ras is also increased during PMA-induced differentiation of HL-60 cells [79] and Ras suppression results in an altered terminal monocytic differentiation and accumulation of atypical monocytes in the blood of Ras suppressor-transduced mice [114]. In CMP and GMP, constitutively active H-Ras and N-Ras variants favor the formation of the monocytic lineage [115]. Human progenitor cells or murine myeloid FDC-P1 cells transduced with constitutively active H-Ras exhibit an enhanced monocyte/macrophage differentiation in vitro, but also tumorigenesis in mice [115, 116]. Comparably, constitutively active K-Ras induces a transient proliferative advantage as well as myelomonocytic differentiation in primary human hematopoietic stem and progenitor cells [117]. Downstream of K-Ras, pro-proliferative effects appear to depend predominantly on ERK, whereas differentiation-supporting effects are mediated via p38 [117]. Transduction of 32D cells with H-Ras or K-Ras induces differentiation towards a monocytic phenotype [118] and primary murine bone marrow-derived cells developed to terminal differentiated macrophages (despite exhibiting an enhanced self-renewal capacity) following H-Ras transduction [119]. Accordingly, bone marrow-depleted mice transplanted with H-Ras-transduced bone marrow cells are characterized by development of (pre-) T and B cell lymphomas but enhanced monocyte and macrophage differentiation [120, 121] whereas N-Ras-transduced mice exhibited hyperproliferation of myeloid cells [122]. In addition, a constitutively active H-Ras variant enhanced susceptibility of human P39 AML cells to ATRA-induced differentiation towards granulocytes and monocytes, presumably in a Raf-independent but protein kinase C (PKC)-dependent manner [123].

Ras-activated Raf family kinases (c-Raf, Raf-A, Raf-B), especially c-Raf, may further contribute to the transduction of both proliferation- and differentiation-supporting signals [107]. For example, it has been shown that c-Raf is involved in proliferation of hematopoietic progenitor cells [124] and the expansion of myeloid progenitors as demonstrated via the formation of myeloid colonies by IL-3- and GM-CSF-treated early hematopoietic progenitor cells [125]. During PMA-induced monocytic differentiation of HL-60 cells, c-Raf is activated [126]. In PMA-resistant HL60 cells undergoing differentiation towards monocytes in response to okadaic acid, c-Raf/MAPK signaling is also enhanced, presumably via an inhibition of serine-threonine phosphatases 1 and 2A [126]. Overexpression of c-Raf enhances both ATRA-dependent granulocyte formation and 1,25(OH)2D3-dependent monocyte formation of HL-60 cells [127]. Moreover, Raf plays a role in later stages of 1,25(OH)2D3-induced monocytic differentiation of HL-60 cells by activating the 90-kDa ribosomal protein S6 kinase in a MEK/ERK-independent manner [128].

Raf subsequently activates MEK1/2, serine and threonine phosphorylating members of the MEK family of kinases predominantly targeting ERK1/2 [107]. In response to pro-proliferative stimuli such as IL-3, MEK-ERK is only transiently activated in 32D cells [129]. In contrast, MEK1/2 and ERK1/2 are perpetually activated in a variety of hematopoietic or leukemia cell lines during granulocytic and monocytic maturation [129, 130]. Inhibition of MEK1/2 suppressed the differentiation of primary human bone marrow-derived cells, 32D, M1, HL-60, and U937 cells towards monocytes in response to several stimuli (e.g., PMA, 1,25(OH)2D3, CDDO, sRAGE, UA) [84, 85, 97, 130–132] as well as macrophage formation of PMA-treated human myeloid leukemia TF-1a cells [133]. ERK1ko mice are characterized by a slight increase in CMP, but a significant decrease in GMP, indicating that ERK1 plays an important role in CMP-to-GMP development [134]. Macrophage formation and function, however, were not impaired. In U937 cells treated with a combination of M-CSF and TNF, a sustained ERK activation correlates with the induction of differentiation [135]. Interestingly, during 1,25(OH)2D3-induced differentiation of HL-60 cells, ERK1/2 are highly activated in a first phase of monocyte development, which is characterized by retained proliferation in combination with the expression of initial differentiation markers [136]. In a second phase, ERK1/2 activation decreased while p27 levels increased, resulting in a block of cell cycle progression and presumably enabling terminal differentiation [136]. The p21- and retinoblastoma protein (Rb) hypophosphorylation-associated inhibition of proliferation during VitE-succinate-induced monocytic differentiation of HL-60 cells also depends on ERK activity [137]. Equivalent results have been observed in HL-60 cells treated with VitD3 derivatives [138]. Mechanistically, differentiation-supporting effects of the Ras-Raf-MEK-ERK cascade are mediated via activation and/or induction of several transcription factors as shown for PU.1, STAT3 [129], C/EBPβ [139], C/EBPα, and c-Fos [140].

MAPK kinase kinase (MAP3K), MAPK kinase (MKK), and JNK

Myelopoiesis and monopoiesis may also be affected by another MAPK pathway, i.e., the MAP3K-MKK-JNK pathway [106]. JNK is predominantly activated by upstream kinases MKK4/7 [106], which in turn are mainly activated by a variety of MAP3K [141]. Effects of JNK family members and their isoforms (p46 isoforms: JNK1α1/β1, JNK2α1/β1, JNK3α1; p54 isoforms: JNK1α2/β2, JNK2α2/β2, JNK3α2) on myelomonocytic differentiation are not comprehensively characterized [42, 141]. However, it is known that JNK is activated during monocytic differentiation of PMA-treated THP-1 and U937 cells [142, 143] or 1,25(OH)2D3-/carnosic acid-treated HL-60 cells [144]. JNK1β1, JNK2α1, and JNK2α2 are predominantly expressed and phosphorylated in LPS-stimulated THP-1-derived monocyte/macrophages [142]. Inhibition of JNK leads to (i) decreased monocytic differentiation of 1,25(OH)2D3-treated HL-60 cells [144], (ii) a reduction of the protein tyrosine phosphatase (PTP) Shp2-induced increased monocytic precursor cell formation in Shp2-transduced murine hematopoietic progenitor cells [145], and (iii) to a markedly reduced formation of macrophages in response to M-CSF in primary murine bone marrow cells [146]. A sustained activation of JNK by HPK1 contributes to cell survival and differentiation of M-CSF-treated primary murine hematopoietic progenitor cells, even in the absence of IL-3 [147]. Recently, it has been shown that JNK activation, e.g., in response to GM-CSF, is also involved in inducing autophagy, a process which is essential for maturation and survival of differentiating primary human blood monocytes [148]. Mechanistically, JNK activity may contribute to differentiation by activating transcription factors of the AP-1 family [144], especially c-Jun, JunB, and JunD [149].

Protein kinase C (PKC) pathway

PKC family kinases are divided into three subgroups: classical/conventional (PKCα, βI, βII, γ), novel (PKCσ, δ, ε, η, θ), and atypical PKC (PKCζ, ι, λ) exhibiting distinct as well as opposing features [150]. A variety of fundamental cellular processes such as proliferation, cell cycle control, and differentiation are controlled by signaling pathways which are (in)directly regulated by PKC family members [150] and PKC represents one of the central molecules involved in myeloid and monocytic differentiation [42].

PKC-dependent signaling

PKC-dependent signaling cascades are classically initiated by GPCR, RTK, or non-receptor tyrosine kinases in response to a variety of stimuli (e.g., CSF, PMA, growth factors, or cytokines) leading to the activation of phospholipase C isoforms (e.g., PLCβ/γ) and the production of diacylglycerol (DAG) and Ca2+-releasing inositol trisphosphate [150]. DAG activates conventional and novel PKC in a Ca2+-dependent (conventional PKC) or -independent (novel PKC) manner whereas atypical PKC are Ca2+/DAG-independent, but respond to ceramide (PKCζ) or activation by src family kinases (SFK) (PKCι/λ). Subsequently, PKC are able to effect further signaling mediators, e.g., GSK3β or Raf1. Thus, several PKC variants may be involved in influencing central cellular features [150] and PKCα and β appear to be the most important isoforms for lineage commitment decisions and maturation of myelomonocytic cells [42]. Following PMA or GM-CSF treatment, PKC, especially PKCα/β, rapidly translocate from the cytosol to the cell membrane in U937 and primary human monocytes and persisting membrane-associated PKC activity is induced [151–153]. During 1,25(OH)2D3-induced monocytic differentiation of HL60 cells, protein expression and activation of PKCα and PKCβ are enhanced [154, 155]. Although PKC activity typically depends on a localization at the cell membrane [156], high PKC activation levels [157] and nuclear PKC localization [158] have been reported to be associated with monocyte/macrophage maturation of GMP, whereas low levels [157] and cytosolic PKC distribution [159] appear to be associated with granulocyte formation. In early hematopoietic precursor cells, however, it has been demonstrated that high PKC activity may favor eosinophil formation, while low PKC activity induces myelomonocytic differentiation [160]. Moreover, during PMA-induced differentiation of U937 cells, PKC appears to contribute to increased cell adherence by inducing integrin hyposialylation in a Ras- and ERK-dependent manner [161]. On the (post)transcriptional level, PKC-dependent effects may be mediated via c-Jun, which is transcriptionally induced following PMA-dependent PKC activation [80], C/EBP proteins that are directly phosphorylated by PKC in vitro [162], or differentiation-associated miRNAs such as miR22 [163].

PKCα- and PKCβ-dependent effects

Selective PKCα activation yields the enhanced maturation of primary human monocyte towards macrophages [152], whereas selective inhibition of PKCα/βI results in the reduced differentiation of primary human monocyte towards macrophages in response to PMA [153]. The transduction of primary GMP with a constitutively active variant of PKCα leads to the development of macrophages even in the presence of granulocyte formation-stimulating agents [164] and PKCα overexpression in 32D cells supports PMA-driven macrophage formation [165]. These effects may be mediated at least in part by PKCα-driven phosphorylation of JNK2 [166] and the subsequent activation of Jun proteins. PKC activation is also associated with proliferation arrest and monocyte differentiation in PMA-stimulated U937 cells [80]. These effects appear to be particularly mediated via PKCβ since PKCβ-deficient U937 cells [167] and PMA-resistant HL-60 cells exhibiting low PKCβ levels [168] are unable to undergo monocytic differentiation in the presence of PMA, an effect which could be resolved by ectopic PKCβ overexpression [167]. Similar effects can be observed in HL60 cells in the presence of a PKCβ-specific inhibitor [169]. Moreover, it has been suggested that macrophage differentiation is associated with PKCβ-dependent expression of extracellular matrix proteins [170].

Src family kinase (SFK) pathway

SFK (Src, Lyn, Fyn, Yes, Fgr, Hck, Lck, Blk, Yrk) are non-receptor protein tyrosine kinases normally attached to the cell membrane and responding to a variety of stimuli, including growth factors, cytokines, and steroids (for review see [171] and [172]). While the majority of SFK is expressed in various cell types including myeloid cells [42], Fgr and Hck appear to be predominantly expressed in cells of the myeloid lineage [173]. Following activation by several types of receptors (e.g., either directly or indirectly by RTK and GPCR) or intracellular kinases such as focal adhesion kinase (FAK), SFK are able to regulate function and activity of a variety of substrates [171, 172]. Thus, SFK may control (i) cell morphology by cytoskeletal rearrangements, (ii) cell motility and adhesion via regulating proteins at focal adhesions or cell–cell contacts, or (iii) translation, metabolism, and proliferation/cell survival via regulating docking/adapter proteins, guanine-nucleotide-exchange factors, or further kinases [42, 171].

Signal integration

One of the most important features of SFK activity is their ability to activate or enhance alternative signaling cascades [42]. For instance, SFK may directly activate STAT proteins in several cell types [174, 175] or indirectly (by recruiting several adapter proteins) the Ras pathway [176], thus potentially driving PU.1, C/EBPα/β, or c-Fos activation. PKC-dependent pathways also appear to be prone to SFK-mediated modulation, since PKC may be activated by Fyn in THP-1 [177] and PKCδ has been shown to be activated by Hck and Lyn in U937 and peripheral blood monocytes [178]. In addition, in various models, it has been reported that SFK are able to phosphorylate RTK (e.g., epidermal growth factor receptor and SCF receptor) [179, 180].

Progenitor cell differentiation

SFK appear to be involved in maintaining cell survival and in the expansion of immature myeloid progenitor cells even under differentiating conditions [42]. In addition, differentiation and differentiation-associated cellular processes such as cytoskeletal rearrangements, adhesion, and migration, may also be effected by SFK [42]. Src, which is an activator of STAT3 and (via FAK/JNK) Jun proteins [172], is significantly induced and activated during PMA-induced monocytic differentiation of U937 and HL-60 cells [181]. Fgr is induced by M-CSF in primary murine monocytic cells and appears to be especially expressed during later developmental stages, whereas Src has been detected during all developmental steps [182]. Hck or Fyn are induced in differentiating THP-1 cells in response to PMA or Bryostatin 1, respectively [177, 183]. Interestingly, overexpression of an inactive Hck variant enhances adherence in U937 cells, whereas constitutively active Hck enhances cell migration [184]. During monocyte/macrophage differentiation of HL-60 cells, SFK expression appears to be stimulus-dependent, since Lyn and Fgr are induced in response to VitD3, whereas Lyn and Fyn are induced in response to PMA [185]. In this context, Lyn and Fyn have been shown to be associated with tubulin phosphorylation and reorganization of microtubules [186] and Lyn has been also suggested to be involved in regulating actin filament polymerization [187]. Lynko mice exhibit increased amounts of immature myeloid progenitor cells (including GMP, promyelocytes, and multilineage progenitors) [188] and susceptibility towards monocyte/macrophage-derived leukemia development [189]. This suggests a role of Lyn in controlling myeloid progenitor proliferation. SFK-dependent effects may be mediated by IRF1, IRF8, and/or c-Jun since it has been demonstrated in DC that these transcription factors can be activated (in)directly by Src family kinases [190]. Lyn has been described to be an activator of PU.1 expression and activity in chicken B cell line DT40 and primary murine splenocytes [191]. In RAW 264.7 cells, SFK such as Hck have been shown to be involved in the activation and binding activity of C/EBPβ, c-Jun, JunB, JunD, and NF-κB subunits c-Rel and p50 [192]. In addition, STAT3 can act as a substrate of Src, Hck, Lyn, and Fyn as demonstrated in SF9 insect cells [193].

Differentiation-associated transcription networks

In the following, prominent transcription factors contributing to progenitor cell expansion and monocyte/macrophage differentiation during different stages of maturation are described (Table 1).

Table 1.

Predominant roles of relevant transcription factors during monocytic differentiation

Purine-rich box 1 (PU.1)

The transcription factor PU.1 is a member of the Ets transcription factor family [194] especially expressed in cells of the myeloid lineage. Although there is no master regulator solely determining myeloid lineage commitment [195], PU.1 appears to be the major regulator of monocytic differentiation [196].

Dose-dependent influence on differentiation

Mice deficient in functional PU.1 are unable to generate maturated cells of the myeloid lineage and die at a late gestational stage or quickly after their birth [197–199]. Expression of PU.1 is increased during early steps of monocyte maturation [200] and essential for CMP formation [201, 202]. PU.1 favors the formation of the myeloid lineage in early developmental steps by inhibiting GATA-1-mediated generation of the erythroid lineage [203, 204] by direct protein–protein interaction [205], whereas PU.1-dependent downregulation of GATA2 gene expression induces macrophage formation and a block of mast cell development [206]. Myeloid progenitor cells transduced with a 4HT-inducible PU.1/ER differentiated towards MDP but not granulocytes in response to 4HT when combined with GM-CSF or IL-3/IL-6/SCF [207]. The impact of PU.1 on myeloid cell maturation appears to be dose dependent, since PU.1-retransduced PU.1ko progenitor cells develop towards monocyte/macrophages in the presence of high PU.1 concentrations, while low PU.1 levels support the formation of B lymphocytes [208]. In this context, high PU.1 expression may be supported by EDAG, which is highly expressed in early stage bone marrow cells and can act as a potent inducer of PU.1, thus favoring myelopoiesis and blocking lymphopoiesis [209]. In addition, high PU.1 amounts in GMP yield the development of monocytes, a phenomenon which may be supported by a positive autoregulatory feedback loop [210], while low levels result in the formation of promyelocytes as precursors of granulocytes [211, 212]. The latter effect could be shown by selective knock out of one PU.1 allele [211], reduction of PU.1 expression by deletion of its distal enhancer [213], or PU.1 elimination in adult mice [201]. Equivalently, in PU.1wt/wt, PU.1wt/ko, and PU.1wt/kd bone marrow-derived myeloid progenitor cells, C/EBPα-induced PU.1 expression yields the formation of monocytic cells, while impaired C/EBPα-induced PU.1 expression in PU.1kd/kd cells (also lacking the distal enhancer) results in the development of granulocytic cells [214]. In an alternative murine model, in which PU.1 expression was considerably reduced by mutation of two (out of three alternative) PU.1 start codons, lymphoid and myeloid cell development was impaired including an expansion and infiltration of immature myeloid cells, e.g., in the spleen of the respective mice [215]. An induction of PU.1 in combination with IRF8 and the initiation of monopoiesis but repression of granulopoiesis can also be created in GMP responding to IFN-γ [216]. Actually, a cooperation of PU.1 and proteins of the IRF family for differentiation-associated gene expression has been demonstrated in promoters containing different Ets/IRF binding sites [217]. During terminal differentiation towards macrophages and granulocytes, however, PU.1 levels are further enhanced in both lineages [200, 211].

Lineage commitment and lineage conversion

Following PU.1 transduction, the expression of high amounts of PU.1 in both hematopoietic progenitors and PU.1ko myeloid progenitors results in the formation of macrophages [208, 218]. Vice versa, PU.1ko HSC exhibit an inhibited CMP development and monocytic differentiation is blocked in PU.1ko CMP or GMP [202]. Murine embryos exclusively expressing inactive variants of PU.1 are characterized by an absence of monocytes in combination with a diminished formation of neutrophil granulocytes [197, 198]. In PU.1ko 503 hematopoietic liver cells, neither the monocytic nor the granulocytic lineage can be formed even in the presence of other differentiation-supporting transcription factors such as C/EBPα [214]. Moreover, it has been shown that PU.1 transduction enables the conversion of B and T lymphocytes into monocytes or macrophages [219–221]. Interestingly, even fibroblasts can be converted into macrophage-like cells if transduced with PU.1 in combination with C/EBPα or C/EBPβ [222].

Potential substitution by other Ets proteins

In vitro cultured PU.1ko murine embryonic stem cells and myeloid progenitors exhibit expression of selected myeloid mRNA species (e.g., GM-CSFR, G-CSFR, and myeloperoxidase) [223] or monocytic differentiation markers (e.g., Ly6C, CD11b, CD18, CD31) [224], respectively. This supports the assumption that other Ets family members, presumably in combination with other differentiation-supporting transcription factors, may be able to compensate (at least in part) for a loss of PU.1 under these conditions [225]. The Ets transcription factor FL-1, for example, plays a role within myeloid lineage commitment decisions since Friend leukemia integration (FLI1)ko mice exhibit (amongst other hematopoietic abnormalities) an increase in monocytic and a decrease in granulocytic progenitors [226] whereas a knock out of the multimeric Ets family member GABP results in a reduced overall amount of myeloid cells [227]. For terminal maturation towards monocytes and granulocytes, however, PU.1 is indispensable [223].

Downstream effects

In part, PU.1 may mediate its differentiation-inducing features by activation of its downstream target KLF4 which is able to initiate monocyte formation in HSC, CMP, and even PU.1ko fetal liver cells, while KLF4 deficiency increased the formation of granulocytes [228]. In proleukemic HSC, PU.1kd is associated with downregulation of c-Jun and JunB as well as the appearance of a myelomonocytic differentiation block, indicating a positive influence of PU.1 on c-Jun and/or JunB expression and potential c-Jun/JunB-mediated effects [229]. Furthermore, a variety of miRNAs is induced or repressed by PU.1 [230]. For instance, PU.1 positively regulates the transcription of miR146a and the miR23a cluster [230, 231]. The latter, coding for miR23a, miR27a, and miR24-2, supports myelopoiesis and inhibits B lymphopoiesis even under B cell formation-promoting conditions [231] whereas ectopic miR146a expression directs adult hematopoietic stem cells selectively to functional peritoneal macrophages in a murine transplantation approach [230]. Moreover, in a zebrafish model, it could be shown that miR146a is also required for myeloid development and macrophage formation during embryogenesis [230].

CCAAT/enhancer binding protein (C/EBP) family

The six members of the C/EBP family (C/EBPα, β, γ, δ, ε, and ξ) are transcription factors of the bZIP type (for review see [232]). While C/EBPγ, δ, and ξ are unique proteins, several isoforms exist of C/EBPα, β, and ε, differing in size and function [232]. C/EBPα-p42 has a higher transactivation capacity than the smaller C/EBPα-p30 variant, which is able to inhibit p42 transactivation potential. Full-length C/EBPβ, i.e., C/EBPβ-LAP*, and the only slightly smaller C/EBPβ-LAP exhibit transactivation activity, whereas C/EBPβ-LIP is transcriptionally inactive and may serve as a dominant-negative inhibitor of LAP*/LAP. Four C/EBPε isoforms with decreasing transactivating capacity are known: p32, p30, p27, and p14 [232]. As homo- or heterodimers, C/EBP family proteins play a relevant role within the process of hematopoiesis and (myelo)monocytic differentiation [43]. C/EBP family members—especially C/EBPα, β, and δ—are strongly expressed in the myeloid lineage and different C/EBP factors appear to play distinct roles during selected stages of myelomonocytic differentiation [43].

C/EBPα

C/EBPα-p42 may facilitate (myelo)monocytic differentiation in an initial step by inhibiting cell cycle progression [233, 234] via inhibition of pro-proliferative factors (e.g., c-Myc) [235], induction of cell cycle inhibitors (e.g., p21) [236], and direct protein–protein interaction with Rb, E2F, and cyclin-dependent kinase (CDK)2/4 [233]. Although it has been reported that C/EBPα-p30 retains the ability to slow myeloid progenitor proliferation despite its limited transactivation potential [237], p42 appears to be required for effective control of myeloid progenitor proliferation [238]. C/EBPα expression is upregulated during early differentiation stages towards the GMP in humans and mice [43, 212] and equivalent results have been obtained in Xenopus [239]. Irradiated mice showed a significant increase in myeloid cells but a decrease in erythroid cells following transplantation of C/EBPα overexpressing bone marrow cells [240]. C/EBPα overexpression in murine erythroleukemia cells induced the expression of myeloid genes and the development of a myeloid-like phenotype [240]. Furthermore, C/EBPα caused a lineage switch towards the myeloid lineage in megakaryocyte-erythroid progenitors [240, 241]. This supports the assumption that C/EBPα suppresses erythroid lineage formation but promotes the determination of the myeloid lineage [240]. Primary murine bone marrow-derived mononuclear cells which were transduced with an estradiol-inducible C/EBPα fusion protein and stimulated with estradiol and myeloid cytokines (IL-3, IL-6, SCF, and/or GM-CSF) exhibited increased numbers of monocytic cells in combination with a reduced amount of granulocytic cells [207]. This effect may be mediated via C/EBPα-induced PU.1 expression as well as the interaction with other transcription factors, e.g., c-Jun and c-Fos [207, 212]. Moreover, it could be shown that the presence of C/EBPα inhibits a further determination of the lymphoid lineage in common lymphoid progenitors (CLP) and (pro-) B cells by antagonizing Pax5, thus promoting the subsequent reprogramming of these cells and the development of pluripotent cells [242] or GMP [219, 243]. In addition, transduction of lymphoid cells like CLP, B cells, and T cells with C/EBPα results in their reprogramming towards monocyte/macrophages [219, 221, 241, 244]. Several knock-out models illustrated that C/EBPαko mice are characterized by an inhibited differentiation of CMP towards GMP, resulting in a reduced number of GMP, MDP, monocytes, and macrophages as well as granulocytes in combination with an accumulation of immature myeloid progenitors [245–247] and cells of the erythroid lineage [240]. Accordingly, inhibition of the intrinsic transactivation capacity of C/EBP family members by application of an inducible, dominant-negative C/EBP inhibitor protein inhibits the formation of GMP, MDP, and granulocyte progenitors in mice as well as the differentiation of murine 32Dcl3 cells towards granulocytes [248]. Interestingly, C/EBPα-p42 does not appear to be essential for CMP-to-GMP transition, since the presence of p30 is sufficient for GMP formation [238]. However, in contrast to p42, p30 presumably posses no further differentiation potential since p30 overexpression attenuated G-CSF-induced differentiation of murine 32D hematopoietic cells in a dose-dependent manner [249]. Moreover, in mice, expression of p30 in the absence of p42 or overexpression of a C/EBPα-p42 variant carrying a mutation in the bZIP region yields the formation of hyperproliferative myeloid progenitors and progression to acute myeloid leukemia [238, 249]. In an alternative study, the enhanced expression of p30 results in a block of myeloid differentiation in human but not in murine primary hematopoietic progenitor cells [250]. In human hematopoietic cells transduced with p30, it has also been shown that p30 is able to provoke the initial steps in myelopoiesis, resulting in the accumulation of myeloblasts and myelocytes, but fails to promote terminal steps of monocytic or granulocytic differentiation [251]. These data also indicate that C/EBPα contributes to myeloid lineage commitment in early and central developmental stages. In later stages, C/EBPα is able to contribute to further differentiation of myelocytes towards monocytes as represented by upregulated C/EBPα levels during monocytic differentiation of mixed lineage leukemia (MLL) fusion gene-positive myelomonoblastic cell lines (i.e., THP-1, MOLM-14, HF-6) [252]. Moreover, in HF-6 and primary AML cells, C/EBPα transduction results in reduced proliferation and enhanced monocytic differentiation [252, 253]. For terminal monocyte maturation, however, C/EBPα appears to be dispensable since Cre recombinase-directed C/EBPα deletion in GMP did not alter the distribution of mature macrophages or granulocytes [246].

C/EBPβ

During myelo-/monopoiesis, different C/EBPβ isoforms appear to regulate multifaceted features in early versus late developmental stages [254]. LIP promotes proliferation in early progenitor cells, as reflected by FLT3L-mediated LIP induction in combination with a decreased LAP/LIP ratio in FLT3wt receptor-transduced 32D hematopoietic cells [92]. These effects can also be found in premonocytic and/or leukemia cells possessing constitutively activating FLT3 mutations such as internal tandem duplications [92]. In contrast, LAP* and LAP suppress (pre)monocytic proliferation by inhibition of c-Myc, E2F1, and cyclin D1/E expression, induction of p27, and interaction with Rb and E2F [255]. In developmental stages providing the formation of both the granulocytic and the monocytic lineage, presence of LAP*/LAP appears to promote the differentiation towards granulocytes since C/EBPβ overexpression in murine bone marrow cells yields an increased formation of granulocytes at the expense of myeloid progenitors which are present in reduced amounts [256, 257]. However, during maturation of (pre)monocytic cells such as MDP, promonocytes, monocytes, and macrophages, LAP* and LAP are prominently expressed [254]. Then, the activation of the larger C/EBPβ isoforms is directly associated with monocytic maturation including the expression of differentiation markers [254], morphological changes [84, 255], and an increasing antimicrobial activity [84]. For instance, in PMA-stimulated NB4 cells, ERK-mediated C/EBPβ expression is involved in inducing Pyk2, a kinase involved in regulating macrophage morphology and migration [258]. For the establishment of the (myelo)monocytic lineage, however, C/EBPβ seems not to be absolutely essential, since C/EBPβko mice are able to produce macrophage-like cells [259, 260]. Immortalized C/EBPβko macrophages derived from C/EBPβko mice, however, exhibit an impaired functionality as reflected by a defective activation in response to activators such as LPS and bacteria [259, 261], impaired induction of differentiation markers [260], and an incomplete development of macrophage morphology [255]. Moreover, the respective mice exhibit an enhanced susceptibility to microbial infections [259, 261]. In addition, formation of myeloid colonies and the amount of generated cells were decreased in C/EBPβko bone marrow-derived progenitor cells [256].

C/EBPε

Another C/EBP family member, C/EBPε, is expressed in both myeloid and lymphoid tissues [262] and may be transcriptionally induced by PU.1 [263]. C/EBPε-p32 has also been shown to negatively regulate the cell cycle and myeloid progenitor proliferation, e.g., by downregulation of c-Myc, CDK4/6, and cyclin A/D2/E in combination with induction of cell cycle inhibitor p27 [264, 265]. Although the influence of different C/EBPε isoforms on (myelo)monocytic differentiation has not been completely elucidated, p32 and p30 appear to be the variants most influencing differentiation processes since they are coexpressed during different myeloid progenitor stages and p30 is specifically upregulated during retinoid-induced differentiation of NB4 cells [266]. Human hematopoietic progenitor cells transduced with different C/EBPε isoforms are able to generate GMP regardless of the respective isoform when treated with SCF, GM-CSF, IL-3, and IL-5 [267]. In addition, the induction of myeloid-specific genes and markers of differentiation (e.g., neutrophil elastase, M-CSFR) may be mediated by p32 and/or p30 in hematopoietic cells, either basal or in response to activating stimuli (e.g., LPS) [266]. Elevated levels of C/EBPε occur during granulocytic versus monocytic lineage determination [268]. Furthermore, C/EBPε-deficient mice demonstrated an enhanced population of actively proliferating bone marrow cells [269], incomplete terminal neutrophil granulocyte differentiation, and impaired macrophage functions [43]. On the other hand, C/EBPε appears to also play a role within the terminal maturation of monocyte/macrophages, since C/EBPε is upregulated during differentiation of MLL-positive myelomonoblasts towards a monocytic phenotype and C/EBPε transduction of HF-6 cells leads to growth arrest and monocyte formation [252]. In addition, other C/EBPεko mouse models solely produce immature and functionally impaired macrophages [270, 271] or an immature intermediate myeloid phenotype exhibiting characteristics of both monocytes and granulocytes [268]. In addition, monocyte/macrophages derived from neutrophil-specific granule deficiency patients carrying homozygous recessive C/EBPε loss-of-function mutations are abnormal in terms of granularity and migration [272]. Consequently, C/EBPε may act as a factor possessing general importance for myeloid lineage determination and terminal differentiation of myeloid cell types [273].

Vitamin D receptor (VDR)

The VDR, which is constitutively expressed in primary human monocytes, but downregulated following differentiation towards macrophages [274], is a member of the nuclear receptor superfamily [275]. Following association with VitD3 derivatives such as 1,25(OH)2D3 [49], VDR is able to directly act together with a coreceptor (retinoic X receptor; RXR) as a heterodimeric transcription factor influencing myeloid differentiation and supporting monocytic lineage commitment [275]. Within the cell, VDR is located in the cytoplasm, the nucleus, or partitioned between both compartments [276]. Upon activation, VDR/RXR heterodimers are able to directly interact with VDRE in the promoters of a variety of VDR-responsive target genes [49, 277].

VDR-mediated inhibition of proliferation

Although it has been reported that 1,25(OH)2D3 is able to promote monocyte proliferation at low concentrations [278] and that HL-60 cells proliferate and expand rapidly in response to 1,25(OH)2D3 [279], alternative vitamin D compounds/analogues as well as higher concentrations of 1,25(OH)2D3 have been shown to inhibit proliferation of NB4, HL-60, U937, and THP-1 cells in a VDR-dependent manner [49, 280, 281]. VDR repression, in turn, significantly decreases antiproliferative effects of 1,25(OH)2D3 [282], which are presumably based on the presence of VDRE in the promoters of cell cycle regulators such as p21, Rb, or p53 [49]. In addition, reduced proliferation of 1,25(OH)2D3-treated HL-60 cells was associated with an increase in VDR but a decrease in c-Myc expression [283]. Accordingly, 1,25(OH)2D3-resistant HL-60 cells were not able to reduce their proliferation and the expression of both genes remained unaffected [283]. The occurrence of 1,25(OH)2D3-induced inhibition of proliferation in combination with cellular differentiation is reflected by enhanced expression of C/EBPβ and Rb in differentiating HL-60 cells [49]. Comparably, monocytic differentiation of U937 cells and increased expression of differentiation markers (e.g., CD14) in response to 1,25(OH)2D3 [282] are associated with VDR-dependent p21 expression [284]. In consequence, 1,25(OH)2D3 and its derivatives are regarded as possible therapeutic tools for the treatment of hyperproliferative disorders such as leukemia [285].

VDR-mediated monocytic differentiation

In 1,25(OH)2D3- or VitD3 derivative-treated HL-60 and U937 cells, VDR-associated reduction of proliferation was accompanied by differentiation towards a monocyte-like phenotype [283, 286]. Treatment of primary human mononuclear blood cells, normal or leukemic primary human myeloid stem/progenitor cells, and HL-60 cells with 1,25(OH)2D3 or fluorinated analogues/derivatives induced their differentiation towards monocytes [287] and macrophages [288, 289]. Stimulation of human bone marrow-derived mononuclear cells, U937, or HL-60 cells with a combination of 1,25(OH)2D3 and ATRA [290–292] or GM-CSF [286, 293] yields monocytic cells but not granulocytes. This phenomenon is presumably mediated by VDR/RXR via the repression of retinoic acid receptor (RAR)/RXR-dependent genes and activation of VDR/RXR-dependent genes [292, 294]. Like granulopoiesis, monocyte-derived DC formation and function are also inhibited by 1,25(OH)2D3 and its analogues in humans and mice [295–297]. In contrast, VDR appears to play a positive role in TGF-β-induced Langerhans cell development [298]. In NB4 cells, it has been shown that differentiation-supporting effects of 1,25(OH)2D3 and other VitD3 derivatives may also be mediated in a VDR-independent manner, i.e., without VDR induction and activation, which suggests an influence of deltanoids on alternative signaling pathways, at least in promyelocytic leukemia cells [299]. VDRko mice are characterized by normal amounts of monocytes and granulocytes, which indicates that myelopoiesis may be induced via alternative pathways under these conditions [300]. Thus, 1,25(OH)2D3-induced VDR activity is not essential for terminal monocyte/granulocyte development in vivo [49]. Nonetheless, functional processes are impaired in VDRko macrophages as demonstrated by decreased IL-18 production [300].

Interferon regulatory factor (IRF) family

The IRF family of transcription factors consists of nine proteins (IRF1-9) (for a detailed review see [217] and [301]). IRF are constitutively expressed in a variety of cell types including myeloid cells, but may be induced in response to a variety of stimuli, e.g., IFN-α/β/γ [217], PMA [302], ATRA [303], GM-CSF, IL-4 [304], or TGF-β [305]. Following activation by phosphorylation, IRF dimerize and translocate to the nucleus, where they can directly act as transcription factors in cooperation with CBP/p300. IRF are involved in regulating immune response and host defense, apoptosis, and tumor suppression, but also cellular differentiation of immune cells. Different combinations of IRF (especially IRF1/4/8) contribute to the formation of myeloid cells, especially granulocytes, macrophages, and DC [217].

Proliferation

IRF family members appear to act as negative regulators of proliferation in myeloid cells [217]. It has been shown in several cell types that IRF1 transactivates p21 expression and cell cycle arrest in cooperation with p53 [306, 307] and induces apoptosis under certain conditions (e.g., in response to IFN-γ) [308]. Overexpression of IRF4 or IRF8 in murine Tot2 myeloid progenitor cells and IRF7 in U937 cells has been demonstrated to induce cell cycle arrest [309–311]. In myeloid (progenitor) cells, IRF8 is able to induce cell cycle inhibitor p15 [312], repressors of c-Myc expression (i.e., BLIMP1 and METS) [313], and neurofibromin 1, a repressor of Ras-associated proliferation [314]. Correspondingly, IRF8-deficient mice are characterized by myeloproliferative disorders [315].

Monocytic differentiation

Maturation of macrophages and DC appears to be influenced particularly by IRF1, 4, and 8 [217]. IRF1 expression is upregulated during monocytic maturation [316] and the expression of several macrophage differentiation markers (e.g., iNOS, Cox2, or CIITA) is IRF1-sensitive [317–319]. IRF1 appears to mediate essential maturation-associated features, since IRF1 repression inhibits PMA-induced monocytic differentiation of U937 cells [302] and IRF1ko bone marrow cells are characterized by increased amounts of immature granulocyte precursor cells [320]. Moreover, their ability to generate further differentiated cells in response to differentiation-inducing stimuli (i.e., M-CSF or G-CSF) is impaired [320]. Mechanistically, this may be connected to reduced expression levels of PU.1, C/EBPα, and C/EBPε which were found in IRF1ko bone marrow cells [320]. Although IRF4ko mice do not exhibit obvious abnormalities in the myeloid lineage, IRF4 appears to contribute to monopoiesis, especially by inhibiting granulocyte formation and during macrophage formation as shown using Tot2 cells [309]. Mice exhibiting both IRF4ko and IRF8ko are characterized by the development of more severe splenomegaly and CML-like leukemia than in IRF8ko mice, including an enhanced proportion of granulocytes [309]. However, since IRF4 is not as strongly expressed as IRF8 in GMP, IRF8 appears to be the more important regulator of monocyte/macrophage maturation [309]. In humans and mice, IRF8 plays a decisive role in concurrently initiating macrophage and DC maturation and suppressing the formation of granulocytes [310, 321, 322], e.g., in response to IFN-γ during inflammation-induced myelopoiesis [216]. This has also been confirmed in alternative models such as zebrafish [323]. Accordingly, IRF8 is significantly expressed in murine hematopoietic progenitor cells during differentiation towards macrophages and further persists in mature macrophages, whereas its expression is reduced in the granulocytic lineage [321]. IRF8 also appears to be regulated by redox signaling, since it has been shown that 12/15-lipoxygenase deficiency leads to impaired IRF8 transactivation activity and reduced monopoiesis in mice [324]. In part, IRF8-dependent effects during monocyte/macrophage differentiation may be mediated via the promyelocytic leukemia protein [325]. IRF8ko mice exhibit reduced amounts of MDP and/or macrophages in combination with increased amounts of immature granulocyte precursor cells and/or neutrophil granulocytes [315, 326] culminating in the development of CML-like blast crisis [315]. In normal mice, injection of IRF8ko blasts yields the development of AML [315], an effect which may be aggravated by constitutive active variants of Shp2 [327]. Moreover, IRF8ko progenitor cells tended to differentiate towards granulocytes even in the presence of M-CSF [326]. This is also reflected in the bone marrow of IRF8ko mice, which is characterized by decreased amounts of cells of the monocytic lineage [326]. However, transduction of IRF8 into IRF8ko bone marrow cells counteracts IRF8ko-dependent effects as represented by increasing monocyte/macrophage formation at the expense of granulocyte formation [321]. IRF8 regulates distinct transcriptional programs in lymphoid and myeloid progenitors [322] and several IRF8-dependent genes adopt a pivotal role for macrophage function, e.g., a variety of enzymes (cathepsin C, lysozyme, cystatin C), cytokines/chemokines (IL-8, IL-12p35/p40, IL-18), and receptors (Toll-like receptor 4/9, FcγR) [217]. During IFN-γ-induced differentiation of U937 cells, IRF8 also mediates protective effects against genotoxic stress by inducing Fanconi F, a protein involved in the repair of cross-linked DNA [328]. IRF1 and especially IRF8 appear to be positive regulators of macrophage maturation, whereas neutrophil formation depends on IRF1 but is inhibited by IRF8 [217].

Signal transducer and activator of transcription (STAT) family

In response to a variety of stimuli, e.g., IFN family members, SCF, M-CSF [329], G-CSF [330], leukemia inhibitory factor (LIF), IL-6, OSM [331], IL-13 [332], and IL-3 [333], (myelo)monocytic differentiation is induced following receptor oligomerization [42] via activation of receptor-bound members of the Janus kinase (JAK) family consisting of JAK1, JAK2, JAK3, and Tyk2 [334]. Following activation, JAK are able to directly activate transcription factors of the STAT family (STAT1, 2, 3, 4, 5A, 5B, 6) by tyrosine phosphorylation.

JAK-dependent effects

JAK1 and Tyk2 appear to play a role for monopoiesis since PTPεC inhibited IL-6- and LIF-induced monocytic differentiation of M1 cells presumably via JAK1 and Tyk2 dephosphorylation [335]. JAK2 has been identified as a positive mediator during GMP formation of the murine multipotent hematopoietic cell line EML in response to IL-3 [336]. JAK3 is upregulated and/or activated during IL-6-induced monocytic differentiation of M1 cells [337]. Furthermore, terminal maturation appears to be JAK3-dependent as shown in JAK3ko mice, which are characterized by increased amounts of immature granulocytic and monocytic progenitor cells [338]. Conversely, JAK3 overexpression yields accelerated macrophage differentiation in GM-CSF-treated primary murine bone marrow cells [337].

STAT1/3-dependent effects

It has been shown that STAT1 is activated during spontaneous or adhesion molecule (laminin, fibronectin)-induced differentiation of primary human monocytes [83] and IFN-γ-induced monocytic differentiation of U937 cells [339]. Interestingly, in this context, differentiation-supporting STAT1 activity appears to depend on JAK-independent serine phosphorylation since tyrosine- and serine-phosphorylated STAT1 is able to induce differentiation marker in human monocytes [83], whereas even constitutive STAT1 tyrosine phosphorylation by Tyk2 overexpression did not enhance STAT1 target gene transcription in U937-derived monocytes [340]. However, in U937 cells constitutively expressing tyrosine phosphorylation-defective STAT1, proliferation arrest and differentiation are inhibited, indicating that STAT1 tyrosine phosphorylation is also of importance, presumably for dimerization and nuclear translocation [341]. During monocyte-to-macrophage differentiation, STAT1 nuclear translocation appears to be specifically mediated by the nuclear shuttle protein nucleolin [342]. Stimulation of human monocytes with the secreted tumor suppressor protein Dickkopf-3 induced STAT1/3 activation and resulted in the differentiation towards a DC-like phenotype [343]. An activation of STAT1, 3, and 5 in murine bone marrow-derived cells is accompanied by an expansion of myeloid cells and an enhanced expression of macrophage differentiation marker [344]. STAT3 appears to be involved in cell cycle arrest by induction of p27 [345] and p19 [346]. During IL-6- and/or LIF-driven growth arrest of M1 cells and differentiation towards macrophages, STAT3 is significantly induced, whereas a dominant-negative STAT3 variant inhibits proliferation stop and differentiation [347, 348]. STAT3 already plays a role during early steps of hematopoiesis as demonstrated by JAK2 and STAT3 activation in erythropoietin-treated murine HSC [349]. Moreover, suppression of STAT3 activity by PTPεC-dependent inhibition of JAK1 and Tyk2 impaired IL-6- and LIF-induced monocytic differentiation of M1 cells [335]. Mice possessing STAT3ko bone marrow cells are characterized by an accumulation of mature (at the expense of immature) neutrophil granulocytes suggesting that STAT3 may act as a restrictor of granulopoiesis [350, 351]. However, neutrophil mobilization in response to G-CSF and chemotactic response to MIP-2 were severely impaired in STAT3ko neutrophils [351] and a reduced anti-inflammatory capacity in STAT3ko macrophages and neutrophils could be determined [352]. STAT3 also induces expression of C/EBPα [353], JunB, and IRF1 [346], thus potentially enhancing its antiproliferative and differentiation-supporting effects.

Activator protein 1 (AP-1) family

AP-1 is a bZIP type transcription factor classically consisting of homo- or heterodimers of the Jun (c-Jun, JunB, JunD) and Fos (c-Fos, FosB, Fra-1, Fra-2) protein families (for review see [354] and [355]). Nonetheless, an interaction with other bZIP transcription factor families, such as JDP (JDP1, JDP2), ATF (ATF1, ATF3, B-ATF), and Maf (c-Maf, Maf-A, -B, -F, -G, -K, Nrl) is also possible [356].

Regulation of proliferation

Overexpression c-Jun in U937 cells or chicken BM2 monoblasts contributes to reduced proliferation rates [357, 358] and equivalent results were obtained in c-Jun and c-Fos expressing U937 or HL-60 cells in response to PMA [151, 359] or tanshinone derivative E278 [360]. In an alternative study, inhibition of c-Jun by antisense approaches was associated with reduced proliferation suggesting a pro-proliferative role of c-Jun in PMA-stimulated U937 cells [361]. In addition, ectopic overexpression of c-Jun in HL-60 cells led to enhanced proliferation, whereas inhibited expression of c-Jun was associated with cell cycle arrest, increased expression of p21, reduced activity of CDK2/4, and attenuated Rb phosphorylation [362]. Therefore, one might speculate that c-Jun mediates pro- and antiproliferative effects under certain but different conditions. JunB mRNA expression is also rapidly and strongly induced in PMA-treated HL-60, THP-1, and U937 cells [363]. JunB or c-Fos overexpression in M1 cells resulted in reduced proliferation rates [364]. Moreover, mice with a myeloid lineage-specific JunBko are characterized by the development of myeloproliferative disease, a phenotype which could be reverted by ectopic JunB expression [365, 366]. The antiproliferative features of JunB may be based on a positive regulation of cell cycle inhibitors (e.g., p16) and/or negative regulation of proliferation-inducing genes (e.g., cyclin D1), either directly or indirectly, as suggested by results obtained in bone marrow-derived mast cells [367]. In proleukemic PU.1kd HSC, it has been shown that a restoration of (originally downregulated) JunB expression is able to suppress leukemic self-renewal capacity and to prevented the development of leukemia in PU.1kd HSC-transplanted NOD-SCID mice [229]. In consequence, JunB may act as a restrictor of excessive myeloid progenitor expansion [366]. Although the influence of JunD on myelomonocytic cell proliferation has not been extensively addressed, it has been shown recently that JunD may also adopt proliferation-restricting functions, since JunD silencing promotes the expansion of 32D cells [368].

Monocytic differentiation

Early it has been shown that Jun proteins are involved in monocytic differentiation since the levels of Jun and Fos proteins are rapidly increased during PMA-induced maturation of U937 and/or HL-60 cells [151, 357], whereas dexamethasone-induced inhibition of U937 differentiation is associated with decreased c-Jun and c-Fos gene expression [369]. Consequently, during differentiation, the amount of functional AP-1 complexes is increased [357] and AP-1 DNA binding activity is enhanced [370]. Besides inhibition of proliferation, overexpression of c-Jun induced monocytic differentiation and function (e.g., phagocytic capacity, nitroblue tetrazolium reduction activity) of myeloid cells such as U937 and HL-60 cells, murine bone marrow-derived cells or myelomonocytic WEHI-3B D + cells [357, 371, 372]. Conversely, Bcr/Abl-mediated inhibition of c-Jun expression resulted in enhanced granulocyte formation as demonstrated in primary human CML granulocytes and KCL22 and K562 CML cell lines, while monocytic differentiation could be induced by c-Jun upregulation [373]. An enhanced myeloid differentiation was also observed in JunB- or c-Fos-transduced M1 cells [364]. An increased granulocyte formation has also been demonstrated in mice with myeloid lineage-specific JunBko [365] but it has been proposed that this might rather reflect the antiproliferative features of JunB [43]. Downregulation of JunD, however, appears to suppress differentiation of 32D cells towards granulocytes even in the presence of G-CSF, suggesting differentiation-supporting characteristics [368].

Network architecture

Although no unique monocyte-forming transcription factor has been identified so far and most of the monopoiesis-inducing factors appear dispensable or replaceable, an essential transcription factor network may be recognized (Fig. 3). The major inducer of monocytic differentiation is PU.1, since it is the first relevant transcription factor appearing in this process [1, 9, 43]. In the course of monocytic differentiation, PU.1 induces other differentiation-supporting factors (e.g., c-Jun, JunB, and C/EBPε) and its presence during monopoiesis may be maintained by positive autoregulation as well as transcription factors such as C/EBPα-p42. Moreover, the effect of several transcription factors is mediated at least in part via cooperation with PU.1 (e.g., C/EBPα, C/EBPβ, IRF proteins, c-Jun, JunB) reflecting the central role of PU.1 in monocyte maturation. Thus, PU.1 facilitates the transition of progenitor cells from one progenitor state to another. Throughout the different stages of monopoiesis, STAT family proteins contribute to PU.1-induced differentiation by preventing excessive progenitor cell expansion (early stages), facilitating progenitor stage transitions, and increasingly inhibiting proliferation of further differentiated progenitors (intermediate/late stages) [42]. However, in each stage, additional factors may provide further transcriptional ‘input’ [9, 43]. Especially in the early stem and progenitor stages (HSC, MPP), factors such as C/EBPα-p30 and C/EBPβ-LIP trigger the required cell expansion, but also the transition towards the directly following progenitors (CMP, GMP). However, for the establishment of the myeloid lineage (CMP), predominantly differentiation-supporting regulators like C/EBPα-p42, VDR, and c-Jun/JunB are required. The formation of pre- and promonocytic cell types as well as monocytes depends on the accessory contribution of C/EBPβ-LAP and proteins of the IRF and STAT families. Finally, terminal differentiation towards macrophages and DC appears to predominantly driven by C/EBPε and IRF8 [9].

Fig. 3.

The influence of key transcription factors on monopoiesis. The figure illustrates the most important transcription factors contributing to progenitor cell expansion (red) and monocyte/macrophage differentiation (blue) during each step of maturation (see text for further details)

Concluding remarks

The present review summarizes specific signaling modules and associated transcription factor networks contributing to (myelo)monocytic differentiation and orchestrating the interplay of proliferation and maturation (Figs. 2, 3). Several signaling modules are involved in mediating proliferation- and/or differentiation-supporting signals, especially PI3K, MAPK, PKC, SFK, JAK, and VDR signaling pathways. Most of them represent powerful, but also general signaling cascades, e.g., MAPK, PI3K, and PKC, regulating a variety of cellular features. Other pathways, e.g., SFK and VDR signaling, cover more specific functionalities such as changes in morphology or expression of effector molecules. Mutual activation of different signaling modules and integration of the variety of complementing or contradictory signals are central aspects affecting monopoiesis. On the transcriptional level, monocyte development is positively or negatively regulated by a network of transcription factors. In the early phase, expansion of immature stem/progenitor cells appears to be governed by C/EBPα-p30 and C/EBPβ-LIP. In the further development, proliferation is progressively restricted and the progenitor cells undergo increasing differentiation, also including the transition towards further differentiated precursors (driven by STAT1/3, C/EBPα-p42, c-Jun/JunB, VDR, IRF1/4/8, and C/EBPβ-LAP). Within the variety of differentiation-supporting transcription factors, PU.1 is the initial and the most powerful mediator of definite monocytic differentiation and represents the key initiator and regulator of monopoiesis. Only for the terminal differentiation towards macrophages and DC, IRF8 and C/EBPε appear to be more influential than PU.1. Together, these findings indicate that the composition of maturation-supporting complexes varies in different developmental steps. It should also be mentioned that beyond regulating transcriptional networks, signaling molecules (e.g., PKC or SFK) may also contribute to monocytic differentiation by directly accessing other regulatory levels or cellular functions which have not been addressed in detail in this article. Due to the complexity and the insufficiently determined composition and precise function of the integrated signaling molecules/transcription factors participating in monocyte/macrophage formation, further studies are necessary to characterize (the combination of) specific conditions and genes/proteins inducing monopoiesis which will presumably elucidate general principles of cellular differentiation. Superior signaling principles and transcription networks may lead to the identification of specific differentiation-associated molecular processes potentially providing further molecular tools for improved diagnostic and therapeutic approaches to assess and/or control inflammatory processes as well as leukemia.

Acknowledgements

We thank Kerstin Püllmann for helpful discussions, Sharon Page for critical reading of the manuscript, and apologize to all authors/working groups whose work has not been considered for this review. This work was supported by the Stiftung für Pathobiochemie und Molekulare Diagnostik der Deutschen Gesellschaft für Klinische Chemie und Laboratoriumsmedizin (DGKL) and by the Deutsche Forschungsgemeinschaft (DFG; SFB 566).

Abbreviations

1,25(OH)2D3

1,25-dihydroxy vitamin D3

4HT

4-hydroxytamoxifen

AML

Acute myeloid leukemia

AP

Activator protein

ATF

Activating transcription factor

ATRA

All-trans retinoic acid

Bcr/Abl

Breakpoint cluster region/Abelson murine leukemia viral oncogene homolog fusion protein

BLIMP

B lymphocyte-induced maturation protein

Bmi

Homolog of B cell-specific Moloney murine leukemia virus integration site

bZIP

Basic leucine zipper

CIITA

Class II major histocompatibility complex transactivator

CBP

CREB binding protein

CD

Cluster of differentiation

CDDO

2-cyano-3,12-dioxooleana-1,9-dien-28-oic acid

CDK

Cyclin-dependent kinase

C/EBP

CCAAT/enhancer binding protein

CLP

Common lymphoid progenitor

CML

Chronic myelogenous leukemia

CMP

Common myeloid progenitor

c-Myc

Avian myelocytomatosis viral oncogene homolog

Cox

Cyclooxygenase

c-Rel

Avian reticuloendotheliosis viral oncogene homolog

CREB

CAMP response element-binding protein

CSF

Colony-stimulating factor

CSFR

CSF receptor

CXCL

C-X-C-motif chemokine ligand

DAG

Diacylgylcerol

DC

Dendritic cell

EDAG

Erythroid differentiation-associated gene

ER

Estrogen receptor

ERK

Extracellular signal-regulated kinase

Ets

E26 transformation-specific

FAK

Focal adhesion kinase

FcγR

Fcγ receptor

FLT3

Fms-like tyrosine kinase 3

FLT3L

FLT3 ligand

Fos

v-Fos murine osteosarcoma viral oncogene homolog

FoxO

Forkhead box protein O

Fra

Fos-related antigen

GABP

GA-binding protein

GATA

GATA-binding factor

G-CSF

Granulocyte CSF

Gfi

Growth factor-independent

GM-CSF

Granulocyte/macrophage CSF

GMP

Granulocyte/monocyte progenitor

GPCR

G protein-coupled receptor

GSK

Glycogen synthase kinase

HIV

Human immunodeficiency virus

Hox

Homeobox

HPK

Hematopoietic progenitor kinase

HSC

Hematopoietic stem cell

IFN

Interferon

IL

Interleukin

iNOS

Inducible nitric oxide synthase

IRF

Interferon regulatory factor

JAK

Janus kinase

JDP

Jun dimerization protein

JNK

c-Jun N-terminal kinase

kd

Knock down

KLF

Krueppel-like factor

ko

Knock out

LAP

Liver-enriched activating protein

LIF

Leukemia inhibitory factor

LIP

Liver-enriched inhibitory protein

LPS

Lipopolysaccharide

Ly6C

Lymphocyte antigen 6 complex locus C

Maf

Musculoaponeurotic fibrosarcoma oncogene homolog

MAPK

Mitogen-activated protein kinase

MAP3K

MAPK kinase kinase

M-CSF

Macrophage-colony stimulating factor

MDP

Monocyte/macrophage and dendritic cell progenitor

MEK

MAPK/ERK kinase

MEP

Megakaryocyte-erythroid progenitor

METS

Mitogenic Ets transcriptional suppressor

MIP

Macrophage inflammatory protein

MKK

MAPK kinase

MLL

Mixed-lineage leukemia

MPP

Multipotent progenitor

mTOR

Mammalian target of rapamycin

NF-κB

Nuclear factor κ-light-chain-enhancer of activated B cells

NOD

Non-obese diabetic

Numb

Homolog of Drosophila Numb

OSM

Oncostatin M

Pax

Paired box protein

PI3K

Phosphoinositide-3-kinase

PIP3

Phosphoinositide-3,4,5-trisphosphate

PKB

Protein kinase B

PKC

Protein kinase C

PMA

Phorbol-12-myristate 13-acetate

PTP

Protein tyrosine phosphatase

PU.1

Purine-rich box 1

PU.1/ER

PU.1/estrogen receptor fusion protein

Pyk

Proline-rich tyrosine kinase

RA

Retinoic acid

Raf

Rapidly accelerated fibrosarcoma

RAR

Retinoic acid receptor

Ras

Rat sarcoma

Rb

Retinoblastoma protein

Rheb

Ras homolog enriched in brain

RSK

90-kDa ribosomal protein S6 kinase

RTK

Receptor tyrosine kinase

RXR

Retinoic X receptor

SCF

Stem cell factor

SCID

Severe combined immunodeficiency

Shp

Src homology 2 domain-containing protein tyrosine phosphatase

SFK

Src family kinase

sRAGE

Soluble receptor for advanced glycation end products

Src

v-Src avian sarcoma viral oncogene homolog

STAT

Signal transducer and activator of transcription

TGF

Transforming growth factor

THOC

THO complex

TNF

Tumor necrosis factor

TSC

Tuberous sclerosis protein

Tyk

Tyrosine kinase

UA

Ursolic acid

VDR

Vitamin D receptor

VDRE

Vitamin D responsive element

Vit

Vitamin

wt

Wild type

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