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Erythroid and megakaryocytic transformation

Oncogene volume 26, pages 6803–6815 (2007)Cite this article

Abstract

Red blood cells and megakaryocytes arise from a common precursor, the megakaryocyte-erythroid progenitor and share many regulators including the transcription factors GATA-1 and GFI-1B and signaling molecules such as JAK2 and STAT5. These lineages also share the distinction of being associated with rare, but aggressive malignancies that have very poor prognoses. In this review, we will briefly summarize features of normal development of red blood cells and megakaryocytes and also highlight events that lead to their leukemic transformation. It is clear that much more work needs to be done to improve our understanding of the unique biology of these leukemias and to pave the way for novel targeted therapeutics.

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References

  • Abdelhaleem M, Beimnet K, Kirby-Allen M, Naqvi A, Hitzler J, Shago M . (2007). High incidence of CALM-AF10 fusion and the identification of a novel fusion transcript in acute megakaryoblastic leukemia in children without Down's syndrome. Leukemia 21: 352–353.

    CAS  PubMed  Google Scholar 

  • Al-Ahmari A, Shah N, Sung L, Zipursky A, Hitzler J . (2006). Long-term results of an ultra low-dose cytarabine-based regimen for the treatment of acute megakaryoblastic leukaemia in children with Down syndrome. Br J Haematol 133: 646–648.

    CAS  PubMed  Google Scholar 

  • Al-Kasim F, Doyle JJ, Massey GV, Weinstein HJ, Zipursky A . (2002). Incidence and treatment of potentially lethal diseases in transient leukemia of Down syndrome: pediatric oncology group study. J Pediatr Hematol Oncol 24: 9–13.

    PubMed  Google Scholar 

  • Andrews NC . (1998). The NF-E2 transcription factor. Int J Biochem Cell Biol 30: 429–432.

    CAS  PubMed  Google Scholar 

  • Aplan PD, Nakahara K, Orkin SH, Kirsch IR . (1992). The SCL gene product: a positive regulator of erythroid differentiation. EMBO J 11: 4073–4081.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Barnard DR, Alonzo TA, Gerbing RB, Lange B, Woods WG . (2006). Comparison of childhood myelodysplastic syndrome, AML FAB M6 or M7, CCG 2891: report from the children's oncology group. Pediatr Blood Cancer 49: 17–22.

    Google Scholar 

  • Baxter EJ, Scott LM, Campbell PJ, East C, Fourouclas N, Swanton S et al. (2005). Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365: 1054–1061.

    Article  CAS  PubMed  Google Scholar 

  • Bernstein J, Dastugue N, Haas OA, Harbott J, Heerema NA, Huret JL et al. (2000). Nineteen cases of the t(1;22)(p13;q13) acute megakaryblastic leukaemia of infants/children and a review of 39 cases: report from a t(1;22) study group. Leukemia 14: 216–218.

    CAS  PubMed  Google Scholar 

  • Blair DG, Athanasiou M . (2000). Ets and retroviruses—transduction and activation of members of the Ets oncogene family in viral oncogenesis. Oncogene 19: 6472–6481.

    CAS  PubMed  Google Scholar 

  • Bourquin JP, Subramanian A, Langebrake C, Reinhardt D, Bernard O, Ballerini P et al. (2006). Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. Proc Natl Acad Sci USA 103: 3339–3344.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cantor AB, Orkin SH . (2002). Transcriptional regulation of erythropoiesis: an affair involving multiple partners. Oncogene 21: 3368–3376.

    CAS  PubMed  Google Scholar 

  • Carpinelli MR, Hilton DJ, Metcalf D, Antonchuk JL, Hyland CD, Mifsud SL et al. (2004). Suppressor screen in Mpl−/− mice: c-Myb mutation causes supraphysiological production of platelets in the absence of thrombopoietin signaling. Proc Natl Acad Sci USA 101: 6553–6558.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Carroll A, Civin C, Schneider N, Dahl G, Pappo A, Bowman P et al. (1991). The t(1;22) (p13;q13) is nonrandom and restricted to infants with acute megakaryoblastic leukemia: a pediatric oncology group study. Blood 78: 748–752.

    CAS  PubMed  Google Scholar 

  • Cen B, Selvaraj A, Burgess RC, Hitzler JK, Ma Z, Morris SW et al. (2003). Megakaryoblastic leukemia 1, a potent transcriptional coactivator for serum response factor (SRF), is required for serum induction of SRF target genes. Mol Cell Biol 23: 6597–6608.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chang AN, Cantor AB, Fujiwara Y, Lodish MB, Droho S, Crispino JD et al. (2002). GATA-factor dependence of the multitype zinc-finger protein FOG-1 for its essential role in megakaryopoiesis. Proc Natl Acad Sci USA 99: 9237–9242.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chen F, Rebay I . (2000). Split ends, a new component of the Drosophila EGF receptor pathway, regulates development of midline glial cells. Curr Biol 10: 943–946.

    CAS  PubMed  Google Scholar 

  • Chen Z, Hu M, Shivdasani RA . (2007). Expression analysis of primary mouse megakaryocyte differentiation and its application in identifying stage-specific molecular markers and a novel transcriptional target of NF-E2. Blood 109: 1451–1459.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Chung SW, Wolff L, Ruscetti SK . (1989). Transmembrane domain of the envelope gene of a polycythemia-inducing retrovirus determines erythropoietin-independent growth. Proc Natl Acad Sci USA 86: 7957–7960.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cramer EM, Norol F, Guichard J, Breton-Gorius J, Vainchenker W, Masse JM et al. (1997). Ultrastructure of platelet formation by human megakaryocytes cultured with the Mpl ligand. Blood 89: 2336–2346.

    CAS  PubMed  Google Scholar 

  • Crispino JD . (2005). GATA1 in normal and malignant hematopoiesis. Semin Cell Dev Biol 16: 137–147.

    CAS  PubMed  Google Scholar 

  • Drexler HG, Matsuo Y, MacLeod RA . (2004). Malignant hematopoietic cell lines: in vitro models for the study of erythroleukemia. Leuk Res 28: 1243–1251.

    CAS  PubMed  Google Scholar 

  • Drissen R, von Lindern M, Kolbus A, Driegen S, Steinlein P, Beug H et al. (2005). The erythroid phenotype of EKLF-null mice: defects in hemoglobin metabolism and membrane stability. Mol Cell Biol 25: 5205–5214.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Du KL, Chen M, Li J, Lepore JJ, Mericko P, Parmacek MS . (2004). Megakaryoblastic leukemia factor-1 transduces cytoskeletal signals and induces smooth muscle cell differentiation from undifferentiated embryonic stem cells. J Biol Chem 279: 17578–17586.

    CAS  PubMed  Google Scholar 

  • Elmaagacli AH, Koldehoff M, Zakrzewski JL, Steckel NK, Ottinger H, Beelen DW . (2007). Growth factor-independent 1B gene (GFI1B) is overexpressed in erythropoietic and megakaryocytic malignancies and increases their proliferation rate. Br J Haematol 136: 212–219.

    CAS  PubMed  Google Scholar 

  • Emambokus N, Vegiopoulos A, Harman B, Jenkinson E, Anderson G, Frampton J . (2003). Progression through key stages of haemopoiesis is dependent on distinct threshold levels of c-Myb. EMBO J 22: 4478–4488.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Fang C, Choi E, Nie L, Li JP . (1998). Role of the transmembrane sequence of spleen focus-forming virus gp55 in erythroleukemogenesis. Virology 252: 46–53.

    CAS  PubMed  Google Scholar 

  • Freyssinier JM, Lecoq-Lafon C, Amsellem S, Picard F, Ducrocq R, Mayeux P et al. (1999). Purification, amplification and characterization of a population of human erythroid progenitors. Br J Haematol 106: 912–922.

    CAS  PubMed  Google Scholar 

  • Friend C . (1957). Cell free transmission in adult Swiss mice of a disease having the character of leukemia. J Exp Med 105: 307–318.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Frohling S, Scholl C, Gilliland DG, Levine RL . (2005). Genetics of myeloid malignancies: pathogenetic and clinical implications. J Clin Oncol 23: 6285–6295.

    CAS  PubMed  Google Scholar 

  • Gamis AS . (2005). Acute myeloid leukemia and Down syndrome evolution of modern therapy—state of the art review. Pediatr Blood Cancer 44: 13–20.

    PubMed  Google Scholar 

  • Garcon L, Lacout C, Svinartchouk F, Le Couedic JP, Villeval JL, Vainchenker W et al. (2005). Gfi-1B plays a critical role in terminal differentiation of normal and transformed erythroid progenitor cells. Blood 105: 1448–1455.

    CAS  PubMed  Google Scholar 

  • Ge Y, Jensen TL, Stout ML, Flatley RM, Grohar PJ, Ravindranath Y et al. (2004). The role of cytidine deaminase and GATA1 mutations in the increased cytosine arabinoside sensitivity of Down syndrome myeloblasts and leukemia cell lines. Cancer Res 64: 728–735.

    CAS  PubMed  Google Scholar 

  • Ghinassi B, Sanchez M, Martelli F, Amabile G, Vannucchi AM, Migliaccio G et al. (2007). The hypomorphic Gata1low mutation alters the proliferation/differentiation potential of the common megakaryocytic-erythroid progenitor. Blood 109: 1460–1471.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Giarratana MC, Kobari L, Lapillonne H, Chalmers D, Kiger L, Cynober T et al. (2005). Ex vivo generation of fully mature human red blood cells from hematopoietic stem cells. Nat Biotechnol 23: 69–74.

    CAS  PubMed  Google Scholar 

  • Goerttler PS, Kreutz C, Donauer J, Faller D, Maiwald T, Marz E et al. (2005). Gene expression profiling in polycythaemia vera: overexpression of transcription factor NF-E2. Br J Haematol 129: 138–150.

    CAS  PubMed  Google Scholar 

  • Growney JD, Shigematsu H, Li Z, Lee BH, Adelsperger J, Rowan R et al. (2005). Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype. Blood 106: 494–504.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Gu TL, Mercher T, Tyner JW, Goss VL, Walters DK, Cornejo MG et al. (2007). A novel fusion of RBM6 to CSF1R in acute megakaryoblastic leukemia. Blood 110: 323–333.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Hancock V, Martin JF, Lelchuk R . (1993). The relationship between human megakaryocyte nuclear DNA content and gene expression. Br J Haematol 85: 692–697.

    CAS  PubMed  Google Scholar 

  • Ichikawa M, Asai T, Saito T, Seo S, Yamazaki I, Yamagata T et al. (2004). AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. Nat Med 10: 299–304.

    CAS  PubMed  Google Scholar 

  • Ito E, Kasai M, Hayashi Y, Toki T, Arai K, Yokoyama S et al. (1995). Expression of erythroid-specific genes in acute megakaryoblastic leukaemia and transient myeloproliferative disorder in Down's syndrome. Br J Haematol 90: 607–614.

    CAS  PubMed  Google Scholar 

  • Izraeli S . (2006). Perspective: chromosomal aneuploidy in leukemia—lessons from Down syndrome. Hematol Oncol 24: 3–6.

    CAS  PubMed  Google Scholar 

  • Jacobs-Helber SM, Roh KH, Bailey D, Dessypris EN, Ryan JJ, Chen J et al. (2003). Tumor necrosis factor-α expressed constitutively in erythroid cells or induced by erythropoietin has negative and stimulatory roles in normal erythropoiesis and erythroleukemia. Blood 101: 524–531.

    CAS  PubMed  Google Scholar 

  • Jaffe ES . (2001). Pathology and Genetics: Tumors of Haematopoietic and Lymphoid Tissues. IARC Press: Lyon.

    Google Scholar 

  • James C, Ugo V, Le Couedic JP, Staerk J, Delhommeau F, Lacout C et al. (2005). A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434: 1144–1148.

    CAS  PubMed  Google Scholar 

  • Jelinek J, Oki Y, Gharibyan V, Bueso-Ramos C, Prchal JT, Verstovsek S et al. (2005). JAK2 mutation 1849G>T is rare in acute leukemias but can be found in CMML, Philadelphia chromosome-negative CML, and megakaryocytic leukemia. Blood 106: 3370–3373.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Keller C, Hansen MS, Coffin CM, Capecchi MR . (2004). Pax3:Fkhr interferes with embryonic Pax3 and Pax7 function: implications for alveolar rhabdomyosarcoma cell of origin. Genes Dev 18: 2608–2613.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Kirito K, Kaushansky K . (2006). Transcriptional regulation of megakaryopoiesis: thrombopoietin signaling and nuclear factors. Curr Opin Hematol 13: 151–156.

    CAS  PubMed  Google Scholar 

  • Kirito K, Nagashima T, Ozawa K, Komatsu N . (2002). Constitutive activation of Stat1 and Stat3 in primary erythroleukemia cells. Int J Hematol 75: 51–54.

    CAS  PubMed  Google Scholar 

  • Kosmider O, Denis N, Lacout C, Vainchenker W, Dubreuil P, Moreau-Gachelin F . (2005). Kit-activating mutations cooperate with Spi-1/PU.1 overexpression to promote tumorigenic progression during erythroleukemia in mice. Cancer Cell 8: 467–478.

    CAS  PubMed  Google Scholar 

  • Koury MJ, Sawyer ST, Bondurant MC . (1984). Splenic erythroblasts in anemia-inducing Friend disease: a source of cells for studies of erythropoietin-mediated differentiation. J Cell Physiol 121: 526–532.

    CAS  PubMed  Google Scholar 

  • Koury MJ, Sawyer ST, Brandt SJ . (2002). New insights into erythropoiesis. Curr Opin Hematol 9: 93–100.

    PubMed  Google Scholar 

  • Kralovics R, Passamonti F, Buser AS, Teo SS, Tiedt R, Passweg JR et al. (2005). A gain-of-function mutation of JAK2 in myeloproliferative disorders. N Engl J Med 352: 1779–1790.

    CAS  PubMed  Google Scholar 

  • Kuhl C, Atzberger A, Iborra F, Nieswandt B, Porcher C, Vyas P . (2005). GATA1-mediated megakaryocyte differentiation and growth control can be uncoupled and mapped to different domains in GATA1. Mol Cell Biol 25: 8592–8606.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Lange B . (2000). The management of neoplastic disorders of haematopoiesis in children with Down's syndrome. Br J Haematol 110: 512–524.

    CAS  PubMed  Google Scholar 

  • Lange BJ, Kobrinsky N, Barnard DR, Arthur DC, Buckley JD, Howells WB et al. (1998). Distinctive demography, biology, and outcome of acute myeloid leukemia and myelodysplastic syndrome in children with Down syndrome: children's cancer group studies 2861 and 2891. Blood 91: 608–615.

    CAS  PubMed  Google Scholar 

  • Langebrake C, Klusmann JH, Wortmann K, Kolar M, Puhlmann U, Reinhardt D . (2006). Concomitant aberrant overexpression of RUNX1 and NCAM in regenerating bone marrow of myeloid leukemia of Down's syndrome. Haematologica 91: 1473–1480.

    CAS  PubMed  Google Scholar 

  • Lannutti BJ, Minear J, Blake N, Drachman JG . (2006). Increased megakaryocytopoiesis in Lyn-deficient mice. Oncogene 25: 3316–3324.

    CAS  PubMed  Google Scholar 

  • Lannutti BJ, Shim MH, Blake N, Reems JA, Drachman JG . (2003). Identification and activation of Src family kinases in primary megakaryocytes. Exp Hematol 31: 1268–1274.

    CAS  PubMed  Google Scholar 

  • Levine RL, Wadleigh M, Cools J, Ebert BL, Wernig G, Huntly BJ et al. (2005). Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7: 387–397.

    CAS  PubMed  Google Scholar 

  • Li Z, Godinho FJ, Klusmann JH, Garriga-Canut M, Yu C, Orkin SH . (2005). Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nat Genet 37: 613–619.

    CAS  PubMed  Google Scholar 

  • Lu SJ, Rowan S, Bani MR, Ben-David Y . (1994). Retroviral integration within the Fli-2 locus results in inactivation of the erythroid transcription factor NF-E2 in Friend erythroleukemias: evidence that NF-E2 is essential for globin expression. Proc Natl Acad Sci USA 91: 8398–8402.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Lulli V, Romania P, Morsilli O, Gabbianelli M, Pagliuca A, Mazzeo S et al. (2006). Overexpression of Ets-1 in human hematopoietic progenitor cells blocks erythroid and promotes megakaryocytic differentiation. Cell Death Differ 13: 1064–1074.

    CAS  PubMed  Google Scholar 

  • Ma X, Renda MJ, Wang L, Cheng EC, Niu C, Morris SW et al. (2007). Rbm15 modulates notch-induced transcriptional activation and affects myeloid differentiation. Mol Cell Biol 27: 3056–3064.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Ma Z, Morris SW, Valentine V, Li M, Herbrick JA, Cui X et al. (2001a). Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28: 220–221.

    CAS  PubMed  Google Scholar 

  • Ma Z, Morris SW, Valentine V, Li M, Herbrick JA, Cui X et al. (2001b). Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nat Genet 28: 220–221.

    CAS  PubMed  Google Scholar 

  • Mahmud DL, M GA, Deb DK, Platanias LC, Uddin S, Wickrema A . (2002). Phosphorylation of forkhead transcription factors by erythropoietin and stem cell factor prevents acetylation and their interaction with coactivator p300 in erythroid progenitor cells. Oncogene 21: 1556–1562.

    CAS  PubMed  Google Scholar 

  • McLean TW, Ringold S, Neuberg D, Stegmaier K, Tantravahi R, Ritz J et al. (1996). TEL/AML-1 dimerizes and is associated with a favorable outcome in childhood acute lymphoblastic leukemia. Blood 88: 4252–4258.

    CAS  PubMed  Google Scholar 

  • Mercher T, Coniat MB, Monni R, Mauchauffe M, Nguyen Khac F, Gressin L et al. (2001). Involvement of a human gene related to the Drosophila spen gene in the recurrent t(1;22) translocation of acute megakaryocytic leukemia. Proc Natl Acad Sci USA 98: 5776–5779.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Michaud J, Wu F, Osato M, Cottles GM, Yanagida M, Asou N et al. (2002). In vitro analyses of known and novel RUNX1/AML1 mutations in dominant familial platelet disorder with predisposition to acute myelogenous leukemia: implications for mechanisms of pathogenesis. Blood 99: 1364–1372.

    CAS  PubMed  Google Scholar 

  • Michiels JJ, van der Meulen J, Brederoo P . (1997). The natural history of trilinear myelodysplastic syndrome and erythroleukemia. Haematologica 82: 452–454.

    CAS  PubMed  Google Scholar 

  • Muntean AG, Crispino JD . (2005). Differential requirements for the activation domain and FOG-interaction surface of GATA-1 in megakaryocyte gene expression and development. Blood 106: 1223–1231.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Muntean AG, Ge Y, Taub JW, Crispino JD . (2006). Transcription factor GATA-1 and Down syndrome leukemogenesis. Leuk Lymphoma 47: 986–997.

    CAS  PubMed  Google Scholar 

  • Muntean AG, Pang L, Poncz M, Dowdy SF, Blobel GA, Crispino JD . (2007). Cyclin D-Cdk4 is regulated by GATA-1 and required for megakaryocyte growth and polyploidization. Blood 109: 5199–5207.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Nelson ME, Steensma DP . (2006). JAK2 V617F in myeloid disorders: what do we know now, and where are we headed? Leuk Lymphoma 47: 177–194.

    CAS  PubMed  Google Scholar 

  • Ney PA, D'Andrea AD . (2000). Friend erythroleukemia revisited. Blood 96: 3675–3680.

    CAS  PubMed  Google Scholar 

  • Nucifora G, Rowley JD . (1995). AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia. Blood 86: 1–14.

    CAS  PubMed  Google Scholar 

  • Oki Y, Kantarjian HM, Zhou X, Cortes J, Faderl S, Verstovsek S et al. (2006). Adult acute megakaryocytic leukemia: an analysis of 37 patients treated at MD Anderson cancer center. Blood 107: 880–884.

    CAS  PubMed  Google Scholar 

  • Osato M, Asou N, Abdalla E, Hoshino K, Yamasaki H, Okubo T et al. (1999). Biallelic and heterozygous point mutations in the runt domain of the AML1 gene associated with myeloblastic leukemias. Blood 93: 1817–1824.

    CAS  PubMed  Google Scholar 

  • Osato M, Ito Y . (2005). Increased dosage of the RUNX1/AML1 gene: a third mode of RUNX leukemia. Crit Rev Eukaryot Gene Expr 15: 217–228.

    CAS  PubMed  Google Scholar 

  • Osawa M, Yamaguchi T, Nakamura Y, Kaneko S, Onodera M, Sawada K et al. (2002). Erythroid expansion mediated by the Gfi-1B zinc finger protein: role in normal hematopoiesis. Blood 100: 2769–2777.

    CAS  PubMed  Google Scholar 

  • Oswald F, Kostezka U, Astrahantseff K, Bourteele S, Dillinger K, Zechner U et al. (2002). SHARP is a novel component of the Notch/RBP-Jκ signalling pathway. EMBO J 21: 5417–5426.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pagano L, Pulsoni A, Vignetti M, Mele L, Fianchi L, Petti MC et al. (2002). Acute megakaryoblastic leukemia: experience of GIMEMA trials. Leukemia 16: 1622–1626.

    CAS  PubMed  Google Scholar 

  • Pang L, Xue HH, Szalai G, Wang X, Wang Y, Watson DK et al. (2006). Maturation stage-specific regulation of megakaryopoiesis by pointed-domain Ets proteins. Blood 108: 2198–2206.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pardanani AD, Levine RL, Lasho T, Pikman Y, Mesa RA, Wadleigh M et al. (2006). MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 108: 3472–3476.

    CAS  PubMed  Google Scholar 

  • Park S, Picard F, Dreyfus F . (2002). Erythroleukemia: a need for a new definition. Leukemia 16: 1399–1401.

    CAS  PubMed  Google Scholar 

  • Peterson LF, Zhang DE . (2004). The 8;21 translocation in leukemogenesis. Oncogene 23: 4255–4262.

    CAS  PubMed  Google Scholar 

  • Phillips JD, Steensma DP, Pulsipher MA, Spangrude GJ, Kushner JP . (2007). Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria. Blood 109: 2618–2621.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Pikman Y, Lee BH, Mercher T, McDowell E, Ebert BL, Gozo M et al. (2006). MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Med 3: e270.

    PubMed Central  PubMed  Google Scholar 

  • Preudhomme C, Warot-Loze D, Roumier C, Grardel-Duflos N, Garand R, Lai JL et al. (2000). High incidence of biallelic point mutations in the Runt domain of the AML1/PEBP2αB gene in Mo acute myeloid leukemia and in myeloid malignancies with acquired trisomy 21. Blood 96: 2862–2869.

    CAS  PubMed  Google Scholar 

  • Putz G, Rosner A, Nuesslein I, Schmitz N, Buchholz F . (2006). AML1 deletion in adult mice causes splenomegaly and lymphomas. Oncogene 25: 929–939.

    CAS  PubMed  Google Scholar 

  • Raffel GD, Mercher T, Shigematsu H, Williams IR, Cullen DE, Akashi K et al. (2007). Ott1(Rbm15) has pleiotropic roles in hematopoietic development. Proc Natl Acad Sci USA 104: 6001–6006.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rainis L, Toki T, Pimanda JE, Rosenthal E, Machol K, Strehl S et al. (2005). The proto-oncogene ERG in megakaryoblastic leukemias. Cancer Res 65: 7596–7602.

    CAS  PubMed  Google Scholar 

  • Raslova H, Kauffmann A, Sekkai D, Ripoche H, Larbret F, Robert T et al. (2006). Interrelation between polyploidization and megakaryocyte differentiation: a gene profiling approach. Blood 109: 3225–3234.

    PubMed  Google Scholar 

  • Raslova H, Roy L, Vourc'h C, Le Couedic JP, Brison O, Metivier D et al. (2003). Megakaryocyte polyploidization is associated with a functional gene amplification. Blood 101: 541–544.

    CAS  PubMed  Google Scholar 

  • Ravid K, Lu J, Zimmet JM, Jones MR . (2002). Roads to polyploidy: the megakaryocyte example. J Cell Physiol 190: 7–20.

    CAS  PubMed  Google Scholar 

  • Rietveld LE, Caldenhoven E, Stunnenberg HG . (2001). Avian erythroleukemia: a model for corepressor function in cancer. Oncogene 20: 3100–3109.

    CAS  PubMed  Google Scholar 

  • Rosenbauer F, Tenen DG . (2007). Transcription factors in myeloid development: balancing differentiation with transformation. Nat Rev Immunol 7: 105–117.

    CAS  PubMed  Google Scholar 

  • Rubnitz JE, Razzouk BI, Lensing S, Pounds S, Pui CH, Ribeiro RC . (2007). Prognostic factors and outcome of recurrence in childhood acute myeloid leukemia. Cancer 109: 157–163.

    PubMed  Google Scholar 

  • Saleque S, Cameron S, Orkin SH . (2002). The zinc-finger proto-oncogene Gfi-1b is essential for development of the erythroid and megakaryocytic lineages. Genes Dev 16: 301–306.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Samarut J, Gazzolo L . (1982). Target cells infected by avian erythroblastosis virus differentiate and become transformed. Cell 28: 921–929.

    CAS  PubMed  Google Scholar 

  • Shivdasani RA, Fujiwara Y, McDevitt MA, Orkin SH . (1997). A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO J 16: 3965–3973.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Shivdasani RA, Rosenblatt MF, Zucker-Franklin D, Jackson CW, Hunt P, Saris CJ et al. (1995). Transcription factor NF-E2 is required for platelet formation independent of the actions of thrombopoietin/MGDF in megakaryocyte development. Cell 81: 695–704.

    CAS  PubMed  Google Scholar 

  • Song WJ, Sullivan MG, Legare RD, Hutchings S, Tan X, Kufrin D et al. (1999). Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nat Genet 23: 166–175.

    CAS  PubMed  Google Scholar 

  • Sotirov N . (1981). Histone H5 in the immature blood cells of chickens with leukosis induced by avian leukosis virus strain E26. J Natl Cancer Inst 66: 1143–1149.

    CAS  PubMed  Google Scholar 

  • Steensma DP, McClure RF, Karp JE, Tefferi A, Lasho TL, Powell HL et al. (2006a). JAK2 V617F is a rare finding in de novo acute myeloid leukemia, but STAT3 activation is common and remains unexplained. Leukemia 20: 971–978.

    CAS  PubMed  Google Scholar 

  • Steensma DP, Pardanani A, Stevenson WS, Hoyt R, Kiu H, Grigg AP et al. (2006b). More on Myb in myelofibrosis: molecular analyses of MYB and EP300 in 55 patients with myeloproliferative disorders. Blood 107: 1733–1735.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sun W, Downing JR . (2004). Haploinsufficiency of AML1 results in a decrease in the number of LTR-HSCs while simultaneously inducing an increase in more mature progenitors. Blood 104: 3565–3572.

    CAS  PubMed  Google Scholar 

  • Szalai G, LaRue AC, Watson DK . (2006). Molecular mechanisms of megakaryopoiesis. Cell Mol Life Sci 63: 2460–2476.

    CAS  PubMed  Google Scholar 

  • Tallman MS, Neuberg D, Bennett JM, Francois CJ, Paietta E, Wiernik PH et al. (2000). Acute megakaryocytic leukemia: the Eastern cooperative oncology group experience. Blood 96: 2405–2411.

    CAS  PubMed  Google Scholar 

  • Teal HE, Ni S, Xu J, Finkelstein LD, Cheng AM, Paulson RF et al. (2006). GRB2-mediated recruitment of GAB2, but not GAB1, to SF-STK supports the expansion of Friend virus-infected erythroid progenitor cells. Oncogene 25: 2433–2443.

    CAS  PubMed  Google Scholar 

  • Tilbrook PA, Palmer GA, Bittorf T, McCarthy DJ, Wright MJ, Sarna MK et al. (2001). Maturation of erythroid cells and erythroleukemia development are affected by the kinase activity of Lyn. Cancer Res 61: 2453–2458.

    CAS  PubMed  Google Scholar 

  • Tsang AP, Fujiwara Y, Hom DB, Orkin SH . (1998). Failure of megakaryopoiesis and arrested erythropoiesis in mice lacking the GATA-1 transcriptional cofactor FOG. Genes Dev 12: 1176–1188.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Tubman VN, Levine JE, Campagna DR, Monahan-Earley R, Dvorak AM, Neufeld EJ et al. (2007). X-linked gray platelet syndrome due to a GATA1 Arg216Gln mutation. Blood 109: 3297–3299.

    CAS  PubMed  Google Scholar 

  • Uddin S, Ah-Kang J, Ulaszek J, Mahmud D, Wickrema A . (2004). Differentiation stage-specific activation of p38 mitogen-activated protein kinase isoforms in primary human erythroid cells. Proc Natl Acad Sci USA 101: 147–152.

    CAS  PubMed  Google Scholar 

  • Vannucchi AM, Bianchi L, Cellai C, Paoletti F, Rana RA, Lorenzini R et al. (2002). Development of myelofibrosis in mice genetically impaired for GATA-1 expression (GATA-1(low) mice). Blood 100: 1123–1132.

    CAS  PubMed  Google Scholar 

  • Vyas P, Ault K, Jackson CW, Orkin SH, Shivdasani RA . (1999). Consequences of GATA-1 deficiency in megakaryocytes and platelets. Blood 93: 2867–2875.

    CAS  PubMed  Google Scholar 

  • Vyas P, Crispino JD . (2007). Molecular insights into Down syndrome-associated leukemia. Curr Opin Pediatr 19: 9–14.

    PubMed  Google Scholar 

  • Vyas P, Roberts I . (2006). Down myeloid disorders: a paradigm for childhood preleukaemia and leukaemia and insights into normal megakaryopoiesis. Early Hum Dev 82: 767–773.

    CAS  PubMed  Google Scholar 

  • Walters DK, Mercher T, Gu TL, O'Hare T, Tyner JW, Loriaux M et al. (2006). Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell 10: 65–75.

    CAS  PubMed  Google Scholar 

  • Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, Le Beau MM et al. (2002). Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32: 148–152.

    CAS  PubMed  Google Scholar 

  • Weiss MJ, Orkin SH . (1995). Transcription factor GATA-1 permits survival and maturation of erythroid precursors by preventing apoptosis. Proc Natl Acad Sci USA 92: 9623–9627.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wickrema A, Bondurant MC, Krantz SB . (1991). Abundance and stability of erythropoietin receptor mRNA in mouse erythroid progenitor cells. Blood 78: 2269–2275.

    CAS  PubMed  Google Scholar 

  • Wickrema A, Krantz SB, Winkelmann JC, Bondurant MC . (1992). Differentiation and erythropoietin receptor gene expression in human erythroid progenitor cells. Blood 80: 1940–1949.

    CAS  PubMed  Google Scholar 

  • Wickrema A, Uddin S, Sharma A, Chen F, Alsayed Y, Ahmad S et al. (1999). Engagement of Gab1 and Gab2 in erythropoietin signaling. J Biol Chem 274: 24469–24474.

    CAS  PubMed  Google Scholar 

  • Wiellette EL, Harding KW, Mace KA, Ronshaugen MR, Wang FY, McGinnis W . (1999). spen encodes an RNP motif protein that interacts with Hox pathways to repress the development of head-like sclerites in the Drosophila trunk. Development 126: 5373–5385.

    CAS  PubMed  Google Scholar 

  • Xu Z, Huang S, Chang LS, Agulnick AD, Brandt SJ . (2003). Identification of a TAL1 target gene reveals a positive role for the LIM domain-binding protein Ldb1 in erythroid gene expression and differentiation. Mol Cell Biol 23: 7585–7599.

    CAS  PubMed Central  PubMed  Google Scholar 

  • Yamashita N, Osato M, Huang L, Yanagida M, Kogan SC, Iwasaki M et al. (2005). Haploinsufficiency of Runx1/AML1 promotes myeloid features and leukaemogenesis in BXH2 mice. Br J Haematol 131: 495–507.

    CAS  PubMed  Google Scholar 

  • Yanagida M, Osato M, Yamashita N, Liqun H, Jacob B, Wu F et al. (2005). Increased dosage of Runx1/AML1 acts as a positive modulator of myeloid leukemogenesis in BXH2 mice. Oncogene 24: 4477–4485.

    CAS  PubMed  Google Scholar 

  • Zhang MY, Sun SC, Bell L, Miller BA . (1998). NF-κB transcription factors are involved in normal erythropoiesis. Blood 91: 4136–4144.

    CAS  PubMed  Google Scholar 

  • Zhao R, Xing S, Li Z, Fu X, Li Q, Krantz SB et al. (2005). Identification of an acquired JAK2 mutation in polycythemia vera. J Biol Chem 280: 22788–22792.

    CAS  PubMed  Google Scholar 

  • Zipursky A . (2003). Transient leukaemia—a benign form of leukaemia in newborn infants with trisomy 21. Br J Haematol 120: 930–938.

    PubMed  Google Scholar 

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Acknowledgements

We thank Dr Koen van Besien for helpful discussions and apologize to those whose work could not be discussed due to space limitations. Dr Wickrema is supported by grants from the NCI and the Leukemia and Lymphoma Society. Dr Crispino is a scholar of the Leukemia and Lymphoma Society and acknowledges support from the NCI and NIDDK.

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  1. Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA

    A Wickrema

  2. Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA

    J D Crispino

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  1. A Wickrema
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  2. J D Crispino
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Correspondence to J D Crispino.

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Wickrema, A., Crispino, J. Erythroid and megakaryocytic transformation. Oncogene 26, 6803–6815 (2007). https://doi.org/10.1038/sj.onc.1210763

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