Rosana Pelayo - Academia.edu (original) (raw)

Papers by Rosana Pelayo

Frontiers in Genetics, 2015

BioMed Research International, 2015

B-cell acute lymphoblastic leukemia (B-ALL) is a serious public health problem in the pediatric p... more B-cell acute lymphoblastic leukemia (B-ALL) is a serious public health problem in the pediatric population worldwide, contributing to 85% of deaths from childhood cancers. Understanding the biology of the disease is crucial for its clinical management and the development of therapeutic strategies. In line with that observed in other malignancies, chronic inflammation may contribute to a tumor microenvironment resulting in the damage of normal processes, concomitant to development and maintenance of neoplastic cells. We report here that hematopoietic cells from bone marrow B-ALL have the ability to produce proinflammatory and growth factors, including TNFα, IL-1β, IL-12, and GM-CSF that stimulate proliferation and differentiation of normal stem and progenitor cells. Our findings suggest an apparently distinct CD13(+)CD33(+) population of leukemic cells contributing to a proinflammatory microenvironment that may be detrimental to long-term normal hematopoiesis within B-ALL bone marrow.

Seminars in immunology, 2006

The production of B cells is a complex process determined by well-timed combinations of intrinsic... more The production of B cells is a complex process determined by well-timed combinations of intrinsic factors and environmental cues that guide the differentiation of primitive progenitors in the bone marrow. Expression of several key transcription factors and receptor-stromal cell ligand interactions are landmarks of the earliest events in B lymphopoiesis in adult bone marrow. We describe this as a gradual loss of options for other blood cell lineages coincident with gain of essential properties. Experimental, stress or infection-related deregulation may change B cell fate specification, commitment or population dynamics, and consequently the production rate of mature populations.

Immunology, 2015

CD38 is a 45-kD transmembrane protein that is expressed in immature and mature lymphocytes. Howev... more CD38 is a 45-kD transmembrane protein that is expressed in immature and mature lymphocytes. However, the expression and function of CD38 during B cell differentiation in mice is poorly understood. Here, we report that CD38 is expressed from the earliest stages of B cell development. Pre-pro-B, pro-B, pre-B, and immature B cells from murine bone marrow all stained positive for CD38.

Stem Cells, 2006

Lymphocyte production in bone marrow (BM) requires substantial cell division, but the relationshi... more Lymphocyte production in bone marrow (BM) requires substantial cell division, but the relationship between largely quiescent stem cells and dividing lymphoid progenitors is poorly understood. Therefore, the proliferation and cell cycle status of murine hematopoietic progenitors that have just initiated the lymphoid differentiation program represented the focus of this study. Continuous bromo-2'-deoxyuridine incorporation (BrdU) and DNA/RNA analysis by flow cytometry revealed that a surprisingly large fraction of RAG-1 + c-kit Hi early lymphoid progenitors (ELP) and RAG-1 + c-kit Lo pro-lymphocytes (Pro-L) in adult BM were in cell cycle quiescence. In contrast, their counterparts in 14 day fetal liver actively proliferated. Indeed, the growth fraction (cells in G 1 -S-G 2 -M phases) of fetal ELP was on average 80% versus only 30% for adult ELP. Following 5fluorouracil treatment, as many as 60% of the adult ELP-enriched population was in G 1 -S-G 2 -M and 34% incorporated BrdU in 6 hours. Transcripts for Bcl-2, p21Cip1/Waf1 and p27 Kip1 cell cycle regulatory genes correlated inversely well with proliferative activity. Interestingly, adult lymphoid progenitors in rebound had the high potential for B lymphopoiesis in culture typical of their fetal counterparts. Thus, lymphocyte production is sustained during adult life by quiescent primitive progenitors that divide intermittently. Some, but not all aspects of the fetal differentiation program are reacquired following chemotherapy.

Seminars in Immunology, 2006

Microbial Pathogenesis, 2009

The Journal of Immunology, 2009

Changes in cell surface markers and patterns of gene expression are commonly used to construct se... more Changes in cell surface markers and patterns of gene expression are commonly used to construct sequences of events in hematopoiesis. However, the order may not be as rigid as once thought and it is unclear which changes represent the best milestones of differentiation. We developed a fate-mapping model where cells with a history of RAG-1 expression are permanently marked by red fluorescence. This approach is valuable for appreciating lymphoid-lineage relationships without need for irradiation and transplantation. Hematopoietic stem cells (HSC) as well as myeloid and dendritic cell progenitors were unlabeled. Also as expected, most previously identified RAG-1 ؉ early lymphoid progenitors in bone marrow and all lymphoid-affiliated cells were marked. Of particular interest, there was heterogeneity among canonical common lymphoid progenitors (CLP) in bone marrow. Labeled CLP expressed slightly higher levels of IL-7R␣, displayed somewhat less c-Kit, and generated CD19 ؉ lymphocytes faster than the unlabeled CLP. Furthermore, CLP with a history of RAG-1 expression were much less likely to generate dendritic and NK cells. The RAG-1-marked CLP were lineage stable even when exposed to LPS, while unlabeled CLP were redirected to become dendritic cells in response to this TLR4 ligand. These findings indicate that essential events in B lymphopoiesis are not tightly synchronized. Some progenitors with increased probability of becoming lymphocytes express RAG-1 while still part of the lineage marker-negative Sca-1 ؉ c-Kit high (LSK) fraction. Other progenitors first activate this locus after c-Kit levels have diminished and cell surface IL-7 receptors are detectable.

The Journal of Immunology, 2005

Current Opinion in Immunology, 2005

Extraordinary progress has been made in charting the maturation of hematopoietic cells. However, ... more Extraordinary progress has been made in charting the maturation of hematopoietic cells. However, these charted processes do not necessarily represent obligate pathways to specialized types of lymphocytes. In fact, there is a degree of plasticity associated with primitive progenitors. Moreover, all lymphocytes of a given kind are not necessarily produced through precisely the same sequence of events. Particularly contentious is the nature of cells that seed the thymus, because different progenitors can generate T cells under experimental circumstances. Non-renewing progenitors with a high density of c-Kit in bone marrow are likely to replenish the thymus under normal circumstances and most closely resemble canonical T cell progenitors.

Blood Cells, Molecules, and Diseases, 2011

In trying to contribute to our knowledge on the role of Notch and its ligands within the human he... more In trying to contribute to our knowledge on the role of Notch and its ligands within the human hematopoietic system, we have assessed the effects of the OP9 stroma cell line - naturally expressing Jagged-1 - transduced with either the Delta-1 gene (OP9-DL1 cells) or with vector alone (OP9-V), on the in vitro growth of two different hematopoietic cell populations. Primitive (CD34(+) CD38(-) Lin(-)) and intermediate (CD34(+) CD38(+) Lin(-)) CD34(+) cell subsets from human cord blood were cultured in the presence of 7 stimulatory cytokines under four different conditions: cytokines alone (control); cytokines and mesenchymal stromal cells; cytokines and OP9-V cells; cytokines and OP9-DL1 cells. Proliferation and expansion were determined after 7days of culture. Culture of CD34(+) CD38(-) Lin(-) cells in the presence of OP9-V or OP9-DL1 cells resulted in a significant increase in the production of new CD34(+) CD38(-) Lin(-) cells (expansion), which expressed increased levels of Notch-1; in contrast, production of total nucleated cells (proliferation) was reduced, as compared to control conditions. In cultures of CD34(+) CD38(+) Lin(-) cells established in the presence of OP9-V or OP9-DL1 cells, expansion was similar to that observed in control conditions, whereas proliferation was also reduced. Interestingly, in these latter cultures we observed production of CD34(+) CD38(-) Lin(-) cells. Our results indicate that, as compared to MSC, OP9 cells were more efficient at inducing self-renewal and/or de novo generation of primitive (CD34(+) CD38(-) Lin(-)) cells, and suggest that such effects were due, at least in part, to the presence of Jagged-1 and DL1.

Blood, 2005

Plasmacytoid dendritic cells (pDCs) competent to make type I interferon were rigorously defined a... more Plasmacytoid dendritic cells (pDCs) competent to make type I interferon were rigorously defined as a Ly-6C(+) and CD11c(Lo) subset of the B220(+)CD19(-) CD43(+)CD24(Lo) bone marrow (BM) Fraction A. Otherwise similar Ly6C(-) cells expressed the natural killer (NK) markers DX5 and NK1.1. pDCs represented a stable, discrete, and long-lived population. Stem cells and early lymphoid progenitors (ELPs), but not prolymphocytes, were effective precursors of pDCs, and their differentiation was blocked by ligation of Notch receptors. Furthermore, pDCs were present in the BM of RAG1(-/-), CD127/IL-7Ra(-/-), and Pax5(-/-) mice. pDCs in RAG1/GFP knock-in mice could be subdivided, and immunoglobulin D(H)-J(H) rearrangements, as well as transcripts for the B-lineage-related genes Pax5, mb1/CD79a, ebf, and Bcl11a, were identified only in the green fluorescent protein-positive (GFP(+)) pDC1 subset. All pDCs expressed terminal deoxynucleotidyl transferase (TdT), the ETS transcription factor Spi-B, the nuclear factor-kappaB transcription factor RelB, toll-like receptor 9 (TLR9), and interferon consensus sequence binding protein (ICSBP)/interferon regulatory factor 8 (IRF-8) transcripts; lacked CD16 and granulocyte colony-stimulating factor receptor (G-CSFR); and were uniformly interleukin-7 receptor alpha (IL-7Ralpha(-)) AA4.1(Lo), CD27(-), Flk-2(Lo), c-Kit(-), DX-5(-), and CD11b(-), while CD4 and CD8alpha were variable. GFP(+) pDC1 subset was less potent than GFP(-) pDC2s in T allostimulation and production of tumor necrosis factor alpha (TNFalpha), interferon alpha (IFNalpha), and interleukin-6 (IL-6), while only pDC2s made IFNgamma and IL-12 p70. Thus, 2 functionally specialized subsets of pDCs arise in bone marrow from progenitors that diverge from B, T, and NK lineages at an early stage.

Rajasekhar/Cancer Stem Cells, 2014