Transcription factors in myeloid development: balancing differentiation with transformation (original) (raw)

• Tenen, D. G., Hromas, R., Licht, J. D. & Zhang, D. E. Transcription factors, normal myeloid development, and leukemia. Blood 90, 489–519 (1997).
  CAS PubMed Google Scholar
• Orkin, S. H. Diversification of haematopoietic stem cells to specific lineages. Nature Rev. Genet. 1, 57–64 (2000).
  Article CAS PubMed Google Scholar
• Tenen, D. G. Disruption of differentiation in human cancer: AML shows the way. Nature Rev. Cancer 3, 89–101 (2003).
  Article CAS Google Scholar
• Kondo, M. et al. Biology of hematopoietic stem cells and progenitors: implications for clinical application. Annu. Rev. Immunol. 21, 759–806 (2003).
  Article CAS PubMed Google Scholar
• Ogawa, M. Differentiation and proliferation of hematopoietic stem cells. Blood 81, 2844–2853 (1993).
  CAS PubMed Google Scholar
• Weissman, I. L., Anderson, D. J. & Gage, F. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annu. Rev. Cell Dev. Biol. 17, 387–403 (2001).
  Article CAS PubMed Google Scholar
• Adolfsson, J. et al. Upregulation of Flt3 expression within the bone marrow Lin−Sca1+c-kit+ stem cell compartment is accompanied by loss of self-renewal capacity. Immunity 15, 659–669 (2001).
  Article CAS PubMed Google Scholar
• Osawa, M., Hanada, K., Hamada, H. & Nakauchi, H. Long-term lymphohematopoietic reconstitution by a single CD34-low/negative hematopoietic stem cell. Science 273, 242–245 (1996).
  Article CAS PubMed Google Scholar
• Morrison, S. J., Uchida, N. & Weissman, I. L. The biology of hematopoietic stem cells. Annu. Rev. Cell Dev. Biol. 11, 35–71 (1995).
  Article CAS PubMed Google Scholar
• Christensen, J. L. & Weissman, I. L. Flk-2 is a marker in hematopoietic stem cell differentiation: a simple method to isolate long-term stem cells. Proc. Natl Acad. Sci. USA 98, 14541–14546 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Lai, A. Y. & Kondo, M. Asymmetrical lymphoid and myeloid lineage commitment in multipotent hematopoietic progenitors. J. Exp. Med. 203, 1867–1873 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Kondo, M., Weissman, I. L. & Akashi, K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661–672 (1997).
  Article CAS PubMed Google Scholar
• Akashi, K., Traver, D., Miyamoto, T. & Weissman, I. L. A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193–197 (2000). References 12 and 13 are the first reports of prospective isolation of the earliest clonogenic lymphoid- and myeloid-restricted progenitor populations, respectively. The methodologies described in these reports are now widely used.
  Article CAS PubMed Google Scholar
• Allman, D. et al. Thymopoiesis independent of common lymphoid progenitors. Nature Immunol. 4, 168–174 (2003).
  Article CAS Google Scholar
• Arinobu, Y. et al. Developmental checkpoints of the basophil/mast cell lineages in adult murine hematopoiesis. Proc. Natl Acad. Sci. USA 102, 18105–18110 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Fogg, D. K. et al. A clonogenic bone marrow progenitor specific for macrophages and dendritic cells. Science 311, 83–87 (2006).
  Article CAS PubMed Google Scholar
• Chen, C. C., Grimbaldeston, M. A., Tsai, M., Weissman, I. L. & Galli, S. J. Identification of mast cell progenitors in adult mice. Proc. Natl Acad. Sci. USA 102, 11408–11413 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Nutt, S. L., Metcalf, D., D'Amico, A., Polli, M. & Wu, L. Dynamic regulation of PU.1 expression in multipotent hematopoietic progenitors. J. Exp. Med. 201, 221–231 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Back, J., Allman, D., Chan, S. & Kastner, P. Visualizing PU.1 activity during hematopoiesis. Exp. Hematol. 33, 395–402 (2005).
  Article CAS PubMed Google Scholar
• Adolfsson, J. et al. Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential a revised road map for adult blood lineage commitment. Cell 121, 295–306 (2005).
  Article CAS PubMed Google Scholar
• Yang, L. et al. Identification of Lin−Sca1+kit+CD34+Flt3− short-term hematopoietic stem cells capable of rapidly reconstituting and rescuing myeloablated transplant recipients. Blood 105, 2717–2723 (2005).
  Article CAS PubMed Google Scholar
• Forsberg, E. C., Serwold, T., Kogan, S., Weissman, I. L. & Passegue, E. New evidence supporting megakaryocyte–erythrocyte potential of flk2/flt3+ multipotent hematopoietic progenitors. Cell 126, 415–426 (2006). References 20 and 22 are two landmark papers that fundamentally differ in their conclusion on the early precursor hierarchy by which the haematopoietic lineages diversify. They are excellent examples that highlight the fact that despite the great progress made, our understanding on these processes is still incomplete.
  Article CAS PubMed Google Scholar
• Iwasaki, H. et al. Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood 106, 1590–1600 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Dakic, A. et al. PU.1 regulates the commitment of adult hematopoietic progenitors and restricts granulopoiesis. J. Exp. Med. 201, 1487–1502 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Klemsz, M. J., McKercher, S. R., Celada, A., van, B. C. & Maki, R. A. The macrophage and B cell-specific transcription factor PU.1 is related to the ets oncogene. Cell 61, 113–124 (1990).
  Article CAS PubMed Google Scholar
• Zhang, D. E. et al. Absence of granulocyte colony-stimulating factor signaling and neutrophil development in CCAAT enhancer binding protein α-deficient mice. Proc. Natl Acad. Sci. USA 94, 569–574 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Tanaka, T. et al. Targeted disruption of the NF-IL6 gene discloses its essential role in bacteria killing and tumor cytotoxicity by macrophages. Cell 80, 353–361 (1995).
  Article CAS PubMed Google Scholar
• Yamanaka, R. et al. Impaired granulopoiesis, myelodysplasia, and early lethality in CCAAT/enhancer binding protein ɛ-deficient mice. Proc. Natl Acad. Sci. USA 94, 13187–13192 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Hock, H. et al. Intrinsic requirement for zinc finger transcription factor Gfi-1 in neutrophil differentiation. Immunity 18, 109–120 (2003).
  Article CAS PubMed Google Scholar
• Holtschke, T. et al. Immunodeficiency and chronic myelogenous leukemia-like syndrome in mice with a targeted mutation of the ICSBP gene. Cell 87, 307–317 (1996). The first example of a knockout mouse of a lineage-specific transcription factor developing myeloid leukaemia.
  Article CAS PubMed Google Scholar
• Okuda, T., van, D. J., Hiebert, S. W., Grosveld, G. & Downing, J. R. AML1, the target of multiple chromosomal translocations in human leukemia, is essential for normal fetal liver hematopoiesis. Cell 84, 321–330 (1996).
  Article CAS PubMed Google Scholar
• Shivdasani, R. A., Mayer, E. L. & Orkin, S. H. Absence of blood formation in mice lacking the T-cell leukaemia oncoprotein tal-1/SCL. Nature 373, 432–434 (1995).
  Article CAS PubMed Google Scholar
• Passegue, E., Jochum, W., Schorpp-Kistner, M., Mohle-Steinlein, U. & Wagner, E. F. Chronic myeloid leukemia with increased granulocyte progenitors in mice lacking junB expression in the myeloid lineage. Cell 104, 21–32 (2001).
  Article CAS PubMed Google Scholar
• Yoshida, T., Ng, S. Y., Zuniga-Pflucker, J. C. & Georgopoulos, K. Early hematopoietic lineage restrictions directed by Ikaros. Nature Immunol. 7, 382–391 (2006).
  Article CAS Google Scholar
• Johansen, L. M. et al. c-Myc is a critical target for c/EBPα in granulopoiesis. Mol. Cell. Biol. 21, 3789–3806 (2001).
  Article CAS PubMed PubMed Central Google Scholar
• Laiosa, C. V., Stadtfeld, M. & Graf, T. Determinants of lymphoid-myeloid lineage diversification. Annu. Rev. Immunol. 24, 705–738 (2006).
  Article CAS PubMed Google Scholar
• Ichikawa, M. et al. AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. Nature Med. 10, 299–304 (2004).
  Article CAS PubMed Google Scholar
• Growney, J. D. et al. Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype. Blood 106, 494–504 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Mikkola, H. K. et al. Haematopoietic stem cells retain long-term repopulating activity and multipotency in the absence of stem-cell leukaemia SCL/tal-1 gene. Nature 421, 547–551 (2003).
  Article CAS PubMed Google Scholar
• Scott, E. W., Simon, M. C., Anastasi, J. & Singh, H. Requirement of transcription factor PU.1 in the development of multiple hematopoietic lineages. Science 265, 1573–1577 (1994).
  Article CAS PubMed Google Scholar
• McKercher, S. R. et al. Targeted disruption of the PU.1 gene results in multiple hematopoietic abnormalities. EMBO J. 15, 5647–5658 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Scott, E. W. et al. PU.1 functions in a cell-autonomous manner to control the differentiation of multipotential lymphoid-myeloid progenitors. Immunity 6, 437–447 (1997).
  Article CAS PubMed Google Scholar
• Iwasaki, H. et al. Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation. Blood 106, 1590–1600 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Rosenbauer, F. et al. Lymphoid cell growth and transformation are suppressed by a key regulatory element of the gene encoding PU.1. Nature Genet. 38, 27–37 (2006).
  Article CAS PubMed Google Scholar
• Moreau-Gachelin, F., Tavitian, A. & Tambourin, P. Spi-1 is a putative oncogene in virally induced murine erythroleukaemias. Nature 331, 277–280 (1988).
  Article CAS PubMed Google Scholar
• Anderson, M. K., Weiss, A. H., Hernandez-Hoyos, G., Dionne, C. J. & Rothenberg, E. V. Constitutive expression of PU.1 in fetal hematopoietic progenitors blocks T cell development at the pro-T cell stage. Immunity 16, 285–296 (2002).
  Article CAS PubMed Google Scholar
• DeKoter, R. P. & Singh, H. Regulation of B lymphocyte and macrophage development by graded expression of PU.1. Science 288, 1439–1441 (2000).
  Article CAS PubMed Google Scholar
• Ye, M., Ermakova, O. & Graf, T. PU.1 is not strictly required for B cell development and its absence induces a B-2 to B-1 cell switch. J. Exp. Med. 202, 1411–1422 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Dahl, R. et al. Regulation of macrophage and neutrophil cell fates by the PU.1:C/EBPα ratio and granulocyte colony-stimulating factor. Nature Immunol. 4, 1029–1036 (2003).
  Article CAS Google Scholar
• Rosenbauer, F. et al. Acute myeloid leukemia induced by graded reduction of a lineage-specific transcription factor, PU.1. Nature Genet. 36, 624–630 (2004). The first report showing that AML can be induced by a decrease in the amount of PU.1.
  Article CAS PubMed Google Scholar
• DeKoter, R. P., Walsh, J. C. & Singh, H. PU.1 regulates both cytokine-dependent proliferation and differentiation of granulocyte/macrophage progenitors. EMBO J. 17, 4456–4468 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Anderson, K. L., Smith, K. A., Pio, F., Torbett, B. E. & Maki, R. A. Neutrophils deficient in PU.1 do not terminally differentiate or become functionally competent. Blood 92, 1576–1585 (1998).
  CAS PubMed Google Scholar
• Radomska, H. S. et al. CCAAT/enhancer binding protein α is a regulatory switch sufficient for induction of granulocytic development from bipotential myeloid progenitors. Mol. Cell. Biol. 18, 4301–4314 (1998).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, P. et al. Enhancement of hematopoietic stem cell repopulating capacity and self-renewal in the absence of the transcription factor C/EBPα. Immunity 21, 853–863 (2004).
  Article CAS PubMed Google Scholar
• Johnson, P. F. Molecular stop signs: regulation of cell-cycle arrest by C/EBP transcription factors. J. Cell Sci. 118, 2545–2555 (2005).
  Article CAS PubMed Google Scholar
• Nerlov, C. C/EBPα mutations in acute myeloid leukaemias. Nature Rev. Cancer 4, 394–400 (2004).
  Article CAS Google Scholar
• Porse, B. T. et al. E2F repression by C/EBPα is required for adipogenesis and granulopoiesis in vivo. Cell 107, 247–258 (2001).
  Article CAS PubMed Google Scholar
• Porse, B. T. et al. The proline-histidine-rich CDK2/CDK4 interaction region of C/EBPα is dispensable for C/EBPα-mediated growth regulation in vivo. Mol. Cell. Biol. 26, 1028–1037 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Driggers, P. H. et al. An interferon γ-regulated protein that binds the interferon-inducible enhancer element of major histocompatibility complex class I genes. Proc. Natl Acad. Sci. USA 87, 3743–3747 (1990).
  Article CAS PubMed PubMed Central Google Scholar
• Tamura, T., Nagamura-Inoue, T., Shmeltzer, Z., Kuwata, T. & Ozato, K. ICSBP directs bipotential myeloid progenitor cells to differentiate into mature macrophages. Immunity 13, 155–165 (2000).
  Article CAS PubMed Google Scholar
• Rosenbauer, F. et al. Interferon consensus sequence binding protein and interferon regulatory factor-4/Pip form a complex that represses the expression of the interferon-stimulated gene-15 in macrophages. Blood 94, 4274–4281 (1999).
  CAS PubMed Google Scholar
• Scharton-Kersten, T., Contursi, C., Masumi, A., Sher, A. & Ozato, K. Interferon consensus sequence binding protein-deficient mice display impaired resistance to intracellular infection due to a primary defect in interleukin 12 p40 induction. J. Exp. Med. 186, 1523–1534 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Giese, N. A. et al. Interferon (IFN) consensus sequence-binding protein, a transcription factor of the IFN regulatory factor family, regulates immune responses in vivo through control of interleukin 12 expression. J. Exp. Med. 186, 1535–1546 (1997).
  Article CAS PubMed PubMed Central Google Scholar
• Scheller, M. et al. Altered development and cytokine responses of myeloid progenitors in the absence of transcription factor, interferon consensus sequence binding protein. Blood 94, 3764–3771 (1999).
  CAS PubMed Google Scholar
• Kallies, A., Rosenbauer, F., Scheller, M., Knobeloch, K. P. & Horak, I. Accumulation of c-Cbl and rapid termination of colony-stimulating factor 1 receptor signaling in interferon consensus sequence binding protein-deficient bone marrow-derived macrophages. Blood 99, 3213–3219 (2002).
  Article CAS PubMed Google Scholar
• Laslo, P. et al. Multilineage transcriptional priming and determination of alternate hematopoietic cell fates. Cell 126, 755–766 (2006).
  Article CAS PubMed Google Scholar
• Zweidler-McKay, P. A., Grimes, H. L., Flubacher, M. M. & Tsichlis, P. N. Gfi-1 encodes a nuclear zinc finger protein that binds DNA and functions as a transcriptional repressor. Mol. Cell. Biol. 16, 4024–4034 (1996).
  Article CAS PubMed PubMed Central Google Scholar
• Karsunky, H., Mende, I., Schmidt, T. & Moroy, T. High levels of the onco-protein Gfi-1 accelerate T-cell proliferation and inhibit activation induced T-cell death in Jurkat T-cells. Oncogene 21, 1571–1579 (2002).
  Article CAS PubMed Google Scholar
• Hock, H. & Orkin, S. H. Zinc-finger transcription factor Gfi-1: versatile regulator of lymphocytes, neutrophils and hematopoietic stem cells. Curr. Opin. Hematol. 13, 1–6 (2006).
  Article CAS PubMed Google Scholar
• Karsunky, H. et al. Inflammatory reactions and severe neutropenia in mice lacking the transcriptional repressor Gfi1. Nature Genet. 30, 295–300 (2002).
  Article PubMed Google Scholar
• Zeng, H., Yucel, R., Kosan, C., Klein-Hitpass, L. & Moroy, T. Transcription factor Gfi1 regulates self-renewal and engraftment of hematopoietic stem cells. EMBO J. 23, 4116–4125 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Hock, H. et al. Gfi-1 restricts proliferation and preserves functional integrity of haematopoietic stem cells. Nature 431, 1002–1007 (2004).
  Article CAS PubMed Google Scholar
• Chen, H. M. et al. Neutrophils and monocytes express high levels of PU.1 (Spi-1) but not Spi-B. Blood 85, 2918–2928 (1995).
  CAS PubMed Google Scholar
• Dahl, R., Ramirez-Bergeron, D. L., Rao, S. & Simon, M. C. Spi-B can functionally replace PU.1 in myeloid but not lymphoid development. EMBO J. 21, 2220–2230 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Jones, L. C. et al. Expression of C/EBPβ from the C/ebp α gene locus is sufficient for normal hematopoiesis in vivo. Blood 99, 2032–2036 (2002).
  Article CAS PubMed Google Scholar
• Hirai, H. et al. C/EBPβ is required for 'emergency' granulopoiesis. Nature Immunol. 7, 732–739 (2006).
  Article CAS Google Scholar
• Li, Y. et al. Regulation of the PU.1 gene by distal elements. Blood 98, 2958–2965 (2001).
  Article CAS PubMed Google Scholar
• Okuno, Y. et al. Potential autoregulation of transcription factor PU.1 by an upstream regulatory element. Mol. Cell. Biol. 25, 2832–2845 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Gottgens, B. et al. Transcriptional regulation of the stem cell leukemia gene (SCL) — comparative analysis of five vertebrate SCL loci. Genome Res. 12, 749–759 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Vyas, P. et al. Different sequence requirements for expression in erythroid and megakaryocytic cells within a regulatory element upstream of the GATA-1 gene. Development 126, 2799–2811 (1999).
  CAS PubMed Google Scholar
• Gottgens, B. et al. The scl +18/19 stem cell enhancer is not required for hematopoiesis: identification of a 5′ bifunctional hematopoietic-endothelial enhancer bound by Fli-1 and Elf-1. Mol. Cell. Biol. 24, 1870–1883 (2004).
  Article PubMed PubMed Central CAS Google Scholar
• Calkhoven, C. F., Muller, C. & Leutz, A. Translational control of gene expression and disease. Trends Mol. Med. 8, 577–583 (2002).
  Article CAS PubMed Google Scholar
• Pabst, T. et al. Dominant-negative mutations of CEBPA, encoding CCAAT/enhancer binding protein-α (C/EBPα), in acute myeloid leukemia. Nature Genet. 27, 263–270 (2001). The first report of CEBPA mutations in patients with AML. It also describes a dominant-negative mechanism that could explain how the mutation of one allele could inhibit the differentiation function of the other (wild-type) allele.
  Article CAS PubMed Google Scholar
• Calkhoven, C. F., Muller, C. & Leutz, A. Translational control of C/EBPα and C/EBPβ isoform expression. Genes Dev. 14, 1920–1932 (2000).
  CAS PubMed PubMed Central Google Scholar
• Calkhoven, C. F. et al. Translational control of SCL-isoform expression in hematopoietic lineage choice. Genes Dev. 17, 959–964 (2003). References 84 and 85 show another mechanism for transcription factor tuning; through varying protein isoform expression, as controlled by small sequence motifs in the untranslated upstream open-reading frames.
  Article CAS PubMed PubMed Central Google Scholar
• Ross, S. E. et al. Phosphorylation of C/EBPα inhibits granulopoiesis. Mol. Cell. Biol. 24, 675–686 (2004).
  Article CAS PubMed PubMed Central Google Scholar
• Behre, G. et al. Ras signaling enhances the activity of C/EBPα to induce granulocytic differentiation by phosphorylation of serine 248. J. Biol. Chem. 277, 26293–26299 (2002).
  Article CAS PubMed Google Scholar
• Rekhtman, N., Radparvar, F., Evans, T. & Skoultchi, A. I. Direct interaction of hematopoietic transcription factors PU.1 and GATA-1: functional antagonism in erythroid cells. Genes Dev. 13, 1398–1411 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Zhang, P. et al. Negative cross-talk between hematopoietic regulators: GATA proteins repress PU.1. Proc. Natl Acad. Sci. USA 96, 8705–8710 (1999).
  Article CAS PubMed PubMed Central Google Scholar
• Stopka, T., Amanatullah, D. F., Papetti, M. & Skoultchi, A. I. PU.1 inhibits the erythroid program by binding to GATA-1 on DNA and creating a repressive chromatin structure. EMBO J. 24, 3712–3723 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Rao, G., Rekhtman, N., Cheng, G., Krasikov, T. & Skoultchi, A. I. Deregulated expression of the PU.1 transcription factor blocks murine erythroleukemia cell terminal differentiation. Oncogene 14, 123–131 (1997).
  Article CAS PubMed Google Scholar
• Zhang, D. E. et al. Function of PU.1 (Spi-1), C/EBP, and AML1 in early myelopoiesis: regulation of multiple myeloid CSF receptor promoters. Curr. Top. Microbiol. Immunol. 211, 137–147 (1996).
  CAS PubMed Google Scholar
• Passegue, E., Jamieson, C. H., Ailles, L. E. & Weissman, I. L. Normal and leukemic hematopoiesis: are leukemias a stem cell disorder or a reacquisition of stem cell characteristics? Proc. Natl Acad. Sci. USA 100 (Suppl. 1), 11842–11849 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Look, A. T. Oncogenic transcription factors in the human acute leukemias. Science 278, 1059–1064 (1997).
  Article CAS PubMed Google Scholar
• Leroy, H. et al. CEBPA point mutations in hematological malignancies. Leukemia 19, 329–334 (2005).
  Article CAS PubMed Google Scholar
• Wechsler, J. et al. Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nature Genet. 32, 148–152 (2002). This paper shows for the first time that acute megakaryoblastic leukaemia associated with Down's syndrome is related to N-terminal mutations in GATA1 that lead to a dominant-negative allele, analogous to CEBPA mutations in the AML FAB system subtype 2.
  Article CAS PubMed Google Scholar
• Crispino, J. D. GATA1 mutations in Down syndrome: implications for biology and diagnosis of children with transient myeloproliferative disorder and acute megakaryoblastic leukemia. Pediatr. Blood Cancer 44, 40–44 (2005).
  Article PubMed Google Scholar
• Calligaris, R., Bottardi, S., Cogoi, S., Apezteguia, I. & Santoro, C. Alternative translation initiation site usage results in two functionally distinct forms of the GATA-1 transcription factor. Proc. Natl Acad. Sci. USA 92, 11598–11602 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Gurbuxani, S., Vyas, P. & Crispino, J. D. Recent insights into the mechanisms of myeloid leukemogenesis in Down syndrome. Blood 103, 399–406 (2004).
  Article CAS PubMed Google Scholar
• Li, Z. et al. Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nature Genet. 37, 613–619 (2005).
  Article CAS PubMed Google Scholar
• Pabst, T. et al. AML1–ETO downregulates the granulocytic differentiation factor C/EBPα in t(8;21) myeloid leukemia. Nature Med. 7, 444–451 (2001).
  Article CAS PubMed Google Scholar
• Mizuki, M. et al. Suppression of myeloid transcription factors and induction of STAT response genes by AML-specific Flt3 mutations. Blood 101, 3164–3173 (2003).
  Article CAS PubMed Google Scholar
• Zheng, R. et al. Internal tandem duplication mutation of FLT3 blocks myeloid differentiation through suppression of C/EBPα expression. Blood 103, 1883–1890 (2004).
  Article CAS PubMed Google Scholar
• Radomska, H. S. et al. Block of C/EBPα function by phosphorylation in acute myeloid leukemia with FLT3 activating mutations. J. Exp. Med. 203, 371–381 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Perrotti, D. et al. BCR–ABL suppresses C/EBPα expression through inhibitory action of hnRNP E2. Nature Genet. 30, 48–58 (2002).
  Article CAS PubMed Google Scholar
• Porse, B. T. et al. Loss of C/EBPα cell cycle control increases myeloid progenitor proliferation and transforms the neutrophil granulocyte lineage. J. Exp. Med. 202, 85–96 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Wagner, K. et al. Absence of the transcription factor CCAAT enhancer binding protein α results in loss of myeloid identity in bcr/abl-induced malignancy. Proc. Natl Acad. Sci. USA 103, 6338–6343 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Osato, M. et al. Biallelic and heterozygous point mutations in the runt domain of the AML1/PEBP2α B gene associated with myeloblastic leukemias. Blood 93, 1817–1824 (1999). This study shows that RUNX1 could be involved in the pathogenesis of AML through a mechanism other than translocation, and that RUNX1 mutations were associated with a distinct differentiation subtype of AML.
  CAS PubMed Google Scholar
• Schmidt, M. et al. Lack of interferon consensus sequence binding protein (ICSBP) transcripts in human myeloid leukemias. Blood 91, 22–29 (1998).
  CAS PubMed Google Scholar
• Hao, S. X. & Ren, R. Expression of interferon consensus sequence binding protein (ICSBP) is downregulated in Bcr–Abl-induced murine chronic myelogenous leukemia-like disease, and forced coexpression of ICSBP inhibits Bcr–Abl-induced myeloproliferative disorder. Mol. Cell. Biol. 20, 1149–1161 (2000).
  Article CAS PubMed PubMed Central Google Scholar
• Schwieger, M. et al. AML1–ETO inhibits maturation of multiple lymphohematopoietic lineages and induces myeloblast transformation in synergy with ICSBP deficiency. J. Exp. Med. 196, 1227–1240 (2002).
  Article CAS PubMed PubMed Central Google Scholar
• Turcotte, K. et al. A mutation in the Icsbp1 gene causes susceptibility to infection and a chronic myeloid leukemia-like syndrome in BXH-2 mice. J. Exp. Med. 201, 881–890 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Mueller, B. U. et al. Heterozygous PU.1 mutations are associated with acute myeloid leukemia. Blood 100, 998–1007 (2002).
  Article CAS PubMed Google Scholar
• Dohner, K. et al. Mutation analysis of the transcription factor PU.1 in younger adults (16 to 60 years) with acute myeloid leukemia: a study of the AML Study Group Ulm (AMLSG ULM). Blood 102, 3850–3851 (2003).
  Article PubMed Google Scholar
• Lamandin, C. et al. Are PU.1 mutations frequent genetic events in acute myeloid leukemia (AML)? Blood 100, 4680–4681 (2002).
  Article CAS PubMed Google Scholar
• Vangala, R. K. et al. The myeloid master regulator transcription factor PU.1 is inactivated by AML1–ETO in t(8;21) myeloid leukemia. Blood 101, 270–277 (2003).
  Article CAS PubMed Google Scholar
• Mueller, B. U. et al. ATRA resolves the differentiation block in t(15;17) acute myeloid leukemia by restoring PU.1 expression. Blood 107, 3330–3338 (2005).
  Article PubMed CAS Google Scholar
• Cook, W. D. et al. PU.1 is a suppressor of myeloid leukemia, inactivated in mice by gene deletion and mutation of its DNA binding domain. Blood 104, 3437–3444 (2004).
  Article CAS PubMed Google Scholar
• Suraweera, N. et al. Mutations of the PU.1 Ets domain are specifically associated with murine radiation-induced, but not human therapy-related, acute myeloid leukaemia. Oncogene 24, 3678–3683 (2005).
  Article CAS PubMed Google Scholar
• Walter, M. J. et al. Reduced PU.1 expression causes myeloid progenitor expansion and increased leukemia penetrance in mice expressing PML–RARα. Proc. Natl Acad. Sci. USA 102, 12513–12518 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Rosenbauer, F., Koschmieder, S., Steidl, U. & Tenen, D. G. Effect of transcription-factor concentrations on leukemic stem cells. Blood 106, 1519–1524 (2005).
  Article CAS PubMed PubMed Central Google Scholar
• Metcalf, D. et al. Inactivation of PU.1 in adult mice leads to the development of myeloid leukemia. Proc. Natl Acad. Sci. USA 103, 1486–1491 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Perkins, A., Kongsuwan, K., Visvader, J., Adams, J. M. & Cory, S. Homeobox gene expression plus autocrine growth factor production elicits myeloid leukemia. Proc. Natl Acad. Sci. USA 87, 8398–8402 (1990).
  Article CAS PubMed PubMed Central Google Scholar
• Chapiro, E. et al. Overexpression of CEBPA resulting from the translocation t(14;19)(q32;q13) of human precursor B acute lymphoblastic leukemia. Blood 108, 3560–3563 (2006).
  Article CAS PubMed Google Scholar
• Chambers, I. & Smith, A. Self-renewal of teratocarcinoma and embryonic stem cells. Oncogene 23, 7150–7160 (2004).
  Article CAS PubMed Google Scholar
• Preudhomme, C. et al. Favorable prognostic significance of CEBPA mutations in patients with de novo acute myeloid leukemia: a study from the Acute Leukemia French Association (ALFA). Blood 100, 2717–2723 (2002).
  Article CAS PubMed Google Scholar
• Duprez, E., Wagner, K., Koch, H. & Tenen, D. G. C/EBPβ: a major PML–RARA-responsive gene in retinoic acid-induced differentiation of APL cells. EMBO J. 22, 5806–5816 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Truong, B. T. et al. CCAAT/enhancer binding proteins repress the leukemic phenotype of acute myeloid leukemia. Blood 101, 1141–1148 (2003).
  Article CAS PubMed Google Scholar
• Lee, Y. J. et al. CCAAT/enhancer binding proteins α and ɛ cooperate with all-trans retinoic acid in therapy but they differ in their anti-leukemic activities. Blood 108, 2416–2419 (2006).
  Article CAS PubMed PubMed Central Google Scholar
• Steffen, B. et al. Specific protein redirection as a transcriptional therapy approach for t(8;21) leukemia. Proc. Natl Acad. Sci. USA 100, 8448–8453 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Krosl, J. et al. In vitro expansion of hematopoietic stem cells by recombinant TAT-HOXB4 protein. Nature Med. 9, 1428–1432 (2003). References 130 and 131 are two elegant studies showing possible ways to design and deliver drugs to modulate transcription factors in cells from cancer patients.
  Article CAS PubMed Google Scholar
• Al-Hasani, K., Vadolas, J., Voullaire, L., Williamson, R. & Ioannou, P. A. Complementation of α-thalassaemia in α-globin knockout mice with a 191 kb transgene containing the human α-globin locus. Transgenic Res. 13, 235–243 (2004).
  Article CAS PubMed Google Scholar
• Robb, L. et al. Absence of yolk sac hematopoiesis from mice with a targeted disruption of the Scl gene. Proc. Natl Acad. Sci. USA 92, 7075–7079 (1995).
  Article CAS PubMed PubMed Central Google Scholar
• Hall, M. A. et al. The critical regulator of embryonic hematopoiesis, SCL, is vital in the adult for megakaryopoiesis, erythropoiesis, and lineage choice in CFU-S12 . Proc. Natl Acad. Sci. USA 100, 992–997 (2003).
  Article CAS PubMed PubMed Central Google Scholar
• Curtis, D. J. et al. SCL is required for normal function of short-term repopulating hematopoietic stem cells. Blood 103, 3342–3348 (2004).
  Article CAS PubMed Google Scholar
• Verbeek, W. et al. Myeloid transcription factor C/EBPɛ is involved in the positive regulation of lactoferrin gene expression in neutrophils. Blood 94, 3141–3150 (1999).
  CAS PubMed Google Scholar
• Speck, N. A. & Gilliland, D. G. Core-binding factors in haematopoiesis and leukaemia. Nature Rev. Cancer 2, 502–513 (2002).
  Article CAS Google Scholar
• Melnick, A. & Licht, J. D. Deconstructing a disease: RARα, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. Blood 93, 3167–3215 (1999).
  CAS PubMed Google Scholar
• Ayton, P. M. & Cleary, M. L. Molecular mechanisms of leukemogenesis mediated by MLL fusion proteins. Oncogene 20, 5695–5707 (2001).
  Article CAS PubMed Google Scholar
• Crispino, J. D. GATA1 in normal and malignant hematopoiesis. Semin. Cell Dev. Biol. 16, 137–147 (2005).
  Article CAS PubMed Google Scholar
• Cilloni, D. et al. Down-modulation of the C/EBPα transcription factor in core binding factor acute myeloid leukemias. Blood 102, 2705–2706 (2003).
  Article CAS PubMed Google Scholar
• Levine, R. L. & Gilliland, D. G. JAK-2 mutations and their relevance to myeloproliferative disease. Curr. Opin. Hematol. 14, 43–47 (2007).
  Article CAS PubMed Google Scholar