Hostname: page-component-cd9895bd7-8ctnn Total loading time: 0 Render date: 2024-12-26T09:28:02.115Z Has data issue: false hasContentIssue false

Normal and malignant megakaryopoiesis

Published online by Cambridge University Press:  21 October 2011

Qiang Wen
Affiliation:
Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA
Benjamin Goldenson
Affiliation:
Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA
John D. Crispino*
Affiliation:
Division of Hematology/Oncology, Northwestern University, Chicago, IL, USA
*
*Corresponding author: John D. Crispino, Division of Hematology/Oncology, Northwestern University, 303 East Superior Street, Lurie 5-113, Chicago, IL 60611, USA. E-mail: j-crispino@northwestern.edu

Abstract

Megakaryopoiesis is the process by which bone marrow progenitor cells develop into mature megakaryocytes (MKs), which in turn produce platelets required for normal haemostasis. Over the past decade, molecular mechanisms that contribute to MK development and differentiation have begun to be elucidated. In this review, we provide an overview of megakaryopoiesis and summarise the latest developments in this field. Specially, we focus on polyploidisation, a unique form of the cell cycle that allows MKs to increase their DNA content, and the genes that regulate this process. In addition, because MKs have an important role in the pathogenesis of acute megakaryocytic leukaemia and a subset of myeloproliferative neoplasms, including essential thrombocythemia and primary myelofibrosis, we discuss the biology and genetics of these disorders. We anticipate that an increased understanding of normal MK differentiation will provide new insights into novel therapeutic approaches that will directly benefit patients.

Type
Review Article
Copyright
Copyright © Cambridge University Press 2011

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

References

1Lichtman, M.A. et al. (2011) Williams Manual of Hematology (8th edn), McGraw-Hill, New YorkGoogle Scholar
2Kanz, L. et al. (1982) Identification of human megakaryocytes derived from pure megakaryocytic colonies (CFU-M), megakaryocytic-erythroid colonies (CFU-M/E), and mixed hemopoietic colonies (CFU-GEMM) by antibodies against platelet associated antigens. Blut 45, 267-274CrossRefGoogle ScholarPubMed
3Nakahata, T., Gross, A.J. and Ogawa, M. (1982) A stochastic model of self-renewal and commitment to differentiation of the primitive hemopoietic stem cells in culture. Journal of Cellular Physiology 113, 455-458CrossRefGoogle ScholarPubMed
4Akashi, K. et al. (2000) A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404, 193-197CrossRefGoogle ScholarPubMed
5Reya, T. et al. (2001) Stem cells, cancer, and cancer stem cells. Nature 414, 105-111CrossRefGoogle ScholarPubMed
6Ogawa, M. (1993) Differentiation and proliferation of hematopoietic stem cells. Blood 81, 2844-2853CrossRefGoogle ScholarPubMed
7Kondo, M., Weissman, I.L. and Akashi, K. (1997) Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661-672CrossRefGoogle ScholarPubMed
8Debili, N. et al. (1996) Characterization of a bipotent erythro-megakaryocytic progenitor in human bone marrow. Blood 88, 1284-1296CrossRefGoogle ScholarPubMed
9Papayannopoulou, T. et al. (1996) Insights into the cellular mechanisms of erythropoietin–thrombopoietin synergy. Experimental Hematology 24, 660-669Google ScholarPubMed
10Adolfsson, J. et al. (2001) 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, 659-669CrossRefGoogle ScholarPubMed
11Adolfsson, J. et al. (2005) Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential a revised road map for adult blood lineage commitment. Cell 121, 295-306CrossRefGoogle ScholarPubMed
12Forsberg, E.C. et al. (2006) New evidence supporting megakaryocyte-erythrocyte potential of flk2/flt3+ multipotent hematopoietic progenitors. Cell 126, 415-426CrossRefGoogle ScholarPubMed
13Nakorn, T.N., Miyamoto, T. and Weissman, I.L. (2003) Characterization of mouse clonogenic megakaryocyte progenitors. Proceedings of the National Academy of Sciences of the United States of America 100, 205-210CrossRefGoogle ScholarPubMed
14Tober, J. et al. (2007) The megakaryocyte lineage originates from hemangioblast precursors and is an integral component both of primitive and of definitive hematopoiesis. Blood 109, 1433-1441CrossRefGoogle ScholarPubMed
15Tober, J., McGrath, K.E. and Palis, J. (2008) Primitive erythropoiesis and megakaryopoiesis in the yolk sac are independent of c-myb. Blood 111, 2636-2639CrossRefGoogle ScholarPubMed
16Xie, X. et al. (2003) Thrombopoietin promotes mixed lineage and megakaryocytic colony-forming cell growth but inhibits primitive and definitive erythropoiesis in cells isolated from early murine yolk sacs. Blood 101, 1329-1335CrossRefGoogle ScholarPubMed
17Vitrat, N. et al. (1998) Endomitosis of human megakaryocytes are due to abortive mitosis. Blood 91, 3711-3723CrossRefGoogle ScholarPubMed
18Harker, L.A. (1968) Kinetics of thrombopoiesis. Journal of Clinical Investigation 47, 458-465CrossRefGoogle ScholarPubMed
19Ebbe, S. et al. (1968) Megakaryocyte maturation rate in thrombocytopenic rats. Blood 32, 787-795CrossRefGoogle ScholarPubMed
20Lordier, L. et al. (2008) Megakaryocyte endomitosis is a failure of late cytokinesis related to defects in the contractile ring and Rho/Rock signaling. Blood 112, 3164-3174CrossRefGoogle ScholarPubMed
21Lordier, L. et al. (2010) Aurora B is dispensable for megakaryocyte polyploidization, but contributes to the endomitotic process. Blood 116, 2345-2355CrossRefGoogle Scholar
22Eliades, A., Papadantonakis, N. and Ravid, K. (2010) New roles for cyclin E in megakaryocytic polyploidization. Journal of Biological Chemistry 285, 18909-18917CrossRefGoogle ScholarPubMed
23Sun, S. et al. (2001) Overexpression of cyclin D1 moderately increases ploidy in megakaryocytes. Haematologica 86, 17-23Google ScholarPubMed
24Zimmet, J.M. et al. (1997) A role for cyclin D3 in the endomitotic cell cycle. Molecular and Cellular Biology 17, 7248-7259CrossRefGoogle ScholarPubMed
25Zimmet, J.M., Toselli, P. and Ravid, K. (1998) Cyclin D3 and megakaryocyte development: exploration of a transgenic phenotype. Stem Cells 16 (Suppl. 2), 97-106CrossRefGoogle ScholarPubMed
26Muntean, A.G. et al. (2007) Cyclin D-Cdk4 is regulated by GATA-1 and required for megakaryocyte growth and polyploidization. Blood 109, 5199-5207CrossRefGoogle ScholarPubMed
27Geng, Y. et al. (2003) Cyclin E ablation in the mouse. Cell 114, 431-443CrossRefGoogle ScholarPubMed
28Chagraoui, H. et al. (2011) SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis. Blood 118, 723-735CrossRefGoogle ScholarPubMed
29Gilles, L. et al. (2008) P19INK4D links endomitotic arrest and megakaryocyte maturation and is regulated by AML-1. Blood 111, 4081-4091CrossRefGoogle ScholarPubMed
30Ganem, N.J., Storchova, Z. and Pellman, D. (2007) Tetraploidy, aneuploidy and cancer. Current Opinion in Genetics and Development 17, 157-162CrossRefGoogle ScholarPubMed
31Ito, D. and Matsumoto, T. (2010) Molecular mechanisms and function of the spindle checkpoint, a guardian of the chromosome stability. Advances in Experimental Medicine and Biology 676, 15-26CrossRefGoogle ScholarPubMed
32Nakaya, T. et al. (2010) Critical role of Pcid2 in B cell survival through the regulation of MAD2 expression. Journal of Immunology 185, 5180-5187CrossRefGoogle Scholar
33Vernole, P. et al. (2009) TAp73alpha binds the kinetochore proteins Bub1 and Bub3 resulting in polyploidy. Cell Cycle 8, 421-429CrossRefGoogle ScholarPubMed
34Wang, Q. et al. (2004) BUBR1 deficiency results in abnormal megakaryopoiesis. Blood 103, 1278-1285CrossRefGoogle ScholarPubMed
35Ruchaud, S., Carmena, M. and Earnshaw, W.C. (2007) Chromosomal passengers: conducting cell division. Nature Reviews. Molecular Cell Biology 8, 798-812CrossRefGoogle ScholarPubMed
36Gurbuxani, S. et al. (2005) Differential requirements for survivin in hematopoietic cell development. Proceedings of the National Academy of Sciences of the United States of America 102, 11480-11485CrossRefGoogle ScholarPubMed
37Wen, Q. et al. (2009) Survivin is not required for the endomitotic cell cycle of megakaryocytes. Blood 114, 153-156CrossRefGoogle Scholar
38Geddis, A.E. and Kaushansky, K. (2004) Megakaryocytes express functional Aurora-B kinase in endomitosis. Blood 104, 1017-1024CrossRefGoogle ScholarPubMed
39Zhang, Y. et al. (2004) Aberrant quantity and localization of Aurora-B/AIM-1 and survivin during megakaryocyte polyploidization and the consequences of Aurora-B/AIM-1-deregulated expression. Blood 103, 3717-3726CrossRefGoogle ScholarPubMed
40Barr, F.A. and Gruneberg, U. (2007) Cytokinesis: placing and making the final cut. Cell 131, 847-860CrossRefGoogle ScholarPubMed
41Burkard, M.E. et al. (2007) Chemical genetics reveals the requirement for Polo-like kinase 1 activity in positioning RhoA and triggering cytokinesis in human cells. Proceedings of the National Academy of Sciences of the United States of America 104, 4383-4388CrossRefGoogle ScholarPubMed
42Lowery, D.M. et al. (2007) Proteomic screen defines the Polo-box domain interactome and identifies Rock2 as a Plk1 substrate. EMBO Journal 26, 2262-2273CrossRefGoogle ScholarPubMed
43Petronczki, M. et al. (2007) Polo-like kinase 1 triggers the initiation of cytokinesis in human cells by promoting recruitment of the RhoGEF Ect2 to the central spindle. Developmental Cell 12, 713-725CrossRefGoogle Scholar
44Yagi, M. and Roth, G.J. (2006) Megakaryocyte polyploidization is associated with decreased expression of polo-like kinase (PLK). Journal of Thrombosis and Haemostasis 4, 2028-2034CrossRefGoogle ScholarPubMed
45Cantor, A.B. and Orkin, S.H. (2002) Transcriptional regulation of erythropoiesis: an affair involving multiple partners. Oncogene 21, 3368-3376CrossRefGoogle ScholarPubMed
46Shivdasani, R.A. et al. (1997) A lineage-selective knockout establishes the critical role of transcription factor GATA-1 in megakaryocyte growth and platelet development. EMBO Journal 16, 3965-3973CrossRefGoogle ScholarPubMed
47Vyas, P. et al. (1999) Different sequence requirements for expression in erythroid and megakaryocytic cells within a regulatory element upstream of the GATA-1 gene. Development 126, 2799-2811CrossRefGoogle ScholarPubMed
48Tsang, A.P. et al. (1998) Failure of megakaryopoiesis and arrested erythropoiesis in mice lacking the GATA-1 transcriptional cofactor FOG. Genes and Development 12, 1176-1188CrossRefGoogle ScholarPubMed
49Chang, A.N. et al. (2002) GATA-factor dependence of the multitype zinc-finger protein FOG-1 for its essential role in megakaryopoiesis. Proceedings of the National Academy of Sciences of the United States of America 99, 9237-9242CrossRefGoogle ScholarPubMed
50Crispino, J.D. (2005) GATA1 in normal and malignant hematopoiesis. Seminars in Cell and Developmental Biology 16, 137-147CrossRefGoogle ScholarPubMed
51Tubman, V.N. et al. (2007) X-linked gray platelet syndrome due to a GATA1 Arg216Gln mutation. Blood 109, 3297-3299CrossRefGoogle ScholarPubMed
52Phillips, J.D. et al. (2007) Congenital erythropoietic porphyria due to a mutation in GATA1: the first trans-acting mutation causative for a human porphyria. Blood 109, 2618-2621CrossRefGoogle ScholarPubMed
53Miccio, A. et al. (2010) NuRD mediates activating and repressive functions of GATA-1 and FOG-1 during blood development. EMBO Journal 29, 442-456CrossRefGoogle ScholarPubMed
54Gregory, G.D. et al. (2010) FOG1 requires NuRD to promote hematopoiesis and maintain lineage fidelity within the megakaryocytic-erythroid compartment. Blood 115, 2156-2166CrossRefGoogle ScholarPubMed
55Tracey, W.D. and Speck, N.A. (2000) Potential roles for RUNX1 and its orthologs in determining hematopoietic cell fate. Seminars in Cell and Developmental Biology 11, 337-342CrossRefGoogle ScholarPubMed
56Kundu, M. et al. (2002) Role of Cbfb in hematopoiesis and perturbations resulting from expression of the leukemogenic fusion gene Cbfb-MYH11. Blood 100, 2449-2456CrossRefGoogle ScholarPubMed
57Elagib, K.E. et al. (2003) RUNX1 and GATA-1 coexpression and cooperation in megakaryocytic differentiation. Blood 101, 4333-4341CrossRefGoogle ScholarPubMed
58Lorsbach, R.B. et al. (2004) Role of RUNX1 in adult hematopoiesis: analysis of RUNX1-IRES-GFP knock-in mice reveals differential lineage expression. Blood 103, 2522-2529CrossRefGoogle ScholarPubMed
59Ichikawa, M. et al. (2004) AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis. Nature Medicine 10, 299-304CrossRefGoogle Scholar
60Growney, J.D. et al. (2005) Loss of Runx1 perturbs adult hematopoiesis and is associated with a myeloproliferative phenotype. Blood 106, 494-504CrossRefGoogle ScholarPubMed
61Putz, G. et al. (2006) AML1 deletion in adult mice causes splenomegaly and lymphomas. Oncogene 25, 929-939CrossRefGoogle ScholarPubMed
62Sun, W. and Downing, J.R. (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, 3565-3572CrossRefGoogle Scholar
63Nucifora, G. and Rowley, J.D. (1995) AML1 and the 8;21 and 3;21 translocations in acute and chronic myeloid leukemia. Blood 86, 1-14CrossRefGoogle Scholar
64Song, W.J. et al. (1999) Haploinsufficiency of CBFA2 causes familial thrombocytopenia with propensity to develop acute myelogenous leukaemia. Nature Genetics 23, 166-175CrossRefGoogle ScholarPubMed
65Peterson, L.F. and Zhang, D.E. (2004) The 8;21 translocation in leukemogenesis. Oncogene 23, 4255-4262CrossRefGoogle Scholar
66Hock, H. et al. (2004) Tel/Etv6 is an essential and selective regulator of adult hematopoietic stem cell survival. Genes and Development 18, 2336-2341CrossRefGoogle ScholarPubMed
67Hart, A. et al. (2000) Fli-1 is required for murine vascular and megakaryocytic development and is hemizygously deleted in patients with thrombocytopenia. Immunity 13, 167-177CrossRefGoogle ScholarPubMed
68Spyropoulos, D.D. et al. (2000) Hemorrhage, impaired hematopoiesis, and lethality in mouse embryos carrying a targeted disruption of the Fli1 transcription factor. Molecular and Cellular Biology 20, 5643-5652CrossRefGoogle ScholarPubMed
69Ano, S. et al. (2004) Erythroblast transformation by FLI-1 depends upon its specific DNA binding and transcriptional activation properties. Journal of Biological Chemistry 279, 2993-3002CrossRefGoogle ScholarPubMed
70Athanasiou, M. et al. (2000) FLI-1 is a suppressor of erythroid differentiation in human hematopoietic cells. Leukemia 14, 439-445CrossRefGoogle ScholarPubMed
71Pang, L. et al. (2006) Maturation stage-specific regulation of megakaryopoiesis by pointed-domain Ets proteins. Blood 108, 2198-2206CrossRefGoogle ScholarPubMed
72Stankiewicz, M.J. and Crispino, J.D. (2009) ETS2 and ERG promote megakaryopoiesis and synergize with alterations in GATA-1 to immortalize hematopoietic progenitor cells. Blood 113, 3337-3347CrossRefGoogle ScholarPubMed
73Salek-Ardakani, S. et al. (2009) ERG is a megakaryocytic oncogene. Cancer Research 69, 4665-4673CrossRefGoogle ScholarPubMed
74Hall, M.A. et al. (2003) The critical regulator of embryonic hematopoiesis, SCL, is vital in the adult for megakaryopoiesis, erythropoiesis, and lineage choice in CFU-S12. Proceedings of the National Academy of Sciences of the United States of America 100, 992-997CrossRefGoogle ScholarPubMed
75Tripic, T. et al. (2009) SCL and associated proteins distinguish active from repressive GATA transcription factor complexes. Blood 113, 2191-2201CrossRefGoogle ScholarPubMed
76Gekas, C. et al. (2009) Mef2C is a lineage-restricted target of Scl/Tal1 and regulates megakaryopoiesis and B-cell homeostasis. Blood 113, 3461-3471CrossRefGoogle ScholarPubMed
77Ma, Z. et al. (2001) Fusion of two novel genes, RBM15 and MKL1, in the t(1;22)(p13;q13) of acute megakaryoblastic leukemia. Nature Genetics 28, 220-221CrossRefGoogle Scholar
78Halene, S. et al. (2010) Serum response factor is an essential transcription factor in megakaryocytic maturation. Blood 116, 1942-1950CrossRefGoogle ScholarPubMed
79Ragu, C. et al. (2010) The serum response factor (SRF)/megakaryocytic acute leukemia (MAL) network participates in megakaryocyte development. Leukemia 24, 1227-1230CrossRefGoogle ScholarPubMed
80Dameshek, W. (1951) Some speculations on the myeloproliferative syndromes. Blood 6, 372-375CrossRefGoogle ScholarPubMed
81Fialkow, P.J., Gartler, S.M. and Yoshida, A. (1967) Clonal origin of chronic myelocytic leukemia in man. Proceedings of the National Academy of Sciences of the United States of America 58, 1468-1471CrossRefGoogle ScholarPubMed
82Gilliland, D.G. et al. (1991) Clonality in myeloproliferative disorders: analysis by means of the polymerase chain reaction. Proceedings of the National Academy of Sciences of the United States of America 88, 6848-6852CrossRefGoogle ScholarPubMed
83Adamson, J.W. et al. (1976) Polycythemia vera: stem-cell and probable clonal origin of the disease. New England Journal of Medicine 295, 913-916CrossRefGoogle ScholarPubMed
84Tefferi, A. (2000) Myelofibrosis with myeloid metaplasia. New England Journal of Medicine 342, 1255-1265CrossRefGoogle ScholarPubMed
85Baxter, E.J. et al. (2005) Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders. Lancet 365, 1054-1061CrossRefGoogle ScholarPubMed
86James, C. et al. (2005) A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera. Nature 434, 1144-1148CrossRefGoogle ScholarPubMed
87Kralovics, R. et al. (2005) A gain-of-function mutation of JAK2 in myeloproliferative disorders. New England Journal of Medicine 352, 1779-1790CrossRefGoogle ScholarPubMed
88Levine, R.L. et al. (2005) Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis. Cancer Cell 7, 387-397CrossRefGoogle ScholarPubMed
89Saharinen, P., Takaluoma, K. and Silvennoinen, O. (2000) Regulation of the Jak2 tyrosine kinase by its pseudokinase domain. Molecular and Cellular Biology 20, 3387-3395CrossRefGoogle ScholarPubMed
90Ihle, J.N. and Gilliland, D.G. (2007) Jak2: normal function and role in hematopoietic disorders. Current Opinion in Genetics and Development 17, 8-14CrossRefGoogle ScholarPubMed
91Scott, L.M. et al. (2006) Progenitors homozygous for the V617F mutation occur in most patients with polycythemia vera, but not essential thrombocythemia. Blood 108, 2435-2437CrossRefGoogle Scholar
92Scott, L.M. et al. (2007) JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis. New England Journal of Medicine 356, 459-468CrossRefGoogle ScholarPubMed
93Wernig, G. et al. (2006) Expression of Jak2V617F causes a polycythemia vera-like disease with associated myelofibrosis in a murine bone marrow transplant model. Blood 107, 4274-4281CrossRefGoogle Scholar
94Tiedt, R. et al. (2008) Ratio of mutant JAK2-V617F to wild-type Jak2 determines the MPD phenotypes in transgenic mice. Blood 111, 3931-3940CrossRefGoogle ScholarPubMed
95Lacout, C. et al. (2006) JAK2V617F expression in murine hematopoietic cells leads to MPD mimicking human PV with secondary myelofibrosis. Blood 108, 1652-1660CrossRefGoogle ScholarPubMed
96Huang, Z. et al. (2007) STAT1 promotes megakaryopoiesis downstream of GATA-1 in mice. Journal of Clinical Investigation 117, 3890-3899CrossRefGoogle ScholarPubMed
97Chen, E. et al. (2010) Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling. Cancer Cell 18, 524-535CrossRefGoogle ScholarPubMed
98Dawson, M.A. et al. (2009) JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. Nature 461, 819-822CrossRefGoogle ScholarPubMed
99Griffiths, D.S. et al. (2011) LIF-independent JAK signalling to chromatin in embryonic stem cells uncovered from an adult stem cell disease. Nature Cell Biology 13, 13-21CrossRefGoogle ScholarPubMed
100Akada, H. et al. (2010) Conditional expression of heterozygous or homozygous Jak2V617F from its endogenous promoter induces a polycythemia vera-like disease. Blood 115, 3589-3597CrossRefGoogle ScholarPubMed
101Li, J. et al. (2010) JAK2 V617F impairs hematopoietic stem cell function in a conditional knock-in mouse model of JAK2 V617F-positive essential thrombocythemia. Blood 116, 1528-1538CrossRefGoogle Scholar
102Marty, C. et al. (2010) Myeloproliferative neoplasm induced by constitutive expression of JAK2V617F in knock-in mice. Blood 116, 783-787CrossRefGoogle ScholarPubMed
103Mullally, A. et al. (2010) Physiological Jak2V617F expression causes a lethal myeloproliferative neoplasm with differential effects on hematopoietic stem and progenitor cells. Cancer Cell 17, 584-596CrossRefGoogle ScholarPubMed
104Pikman, Y. et al. (2006) MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia. PLoS Medicine 3, e270CrossRefGoogle ScholarPubMed
105Chaligne, R. et al. (2008) New mutations of MPL in primitive myelofibrosis: only the MPL W515 mutations promote a G1/S-phase transition. Leukemia 22, 1557-1566CrossRefGoogle ScholarPubMed
106Pardanani, A.D. et al. (2006) MPL515 mutations in myeloproliferative and other myeloid disorders: a study of 1182 patients. Blood 108, 3472-3476CrossRefGoogle ScholarPubMed
107Beer, P.A. et al. (2008) MPL mutations in myeloproliferative disorders: analysis of the PT-1 cohort. Blood 112, 141-149CrossRefGoogle ScholarPubMed
108Ding, J. et al. (2004) Familial essential thrombocythemia associated with a dominant-positive activating mutation of the c-MPL gene, which encodes for the receptor for thrombopoietin. Blood 103, 4198-4200CrossRefGoogle ScholarPubMed
109Vannucchi, A.M. et al. (2008) Characteristics and clinical correlates of MPL 515W > L/K mutation in essential thrombocythemia. Blood 112, 844-847CrossRefGoogle ScholarPubMed
110Guglielmelli, P. et al. (2007) Anaemia characterises patients with myelofibrosis harbouring Mpl mutation. British Journal of Haematology 137, 244-247CrossRefGoogle ScholarPubMed
111Takaki, S. et al. (2002) Enhanced hematopoiesis by hematopoietic progenitor cells lacking intracellular adaptor protein, Lnk. Journal of Experimental Medicine 195, 151-160CrossRefGoogle ScholarPubMed
112Tong, W. and Lodish, H.F. (2004) Lnk inhibits Tpo-mpl signaling and Tpo-mediated megakaryocytopoiesis. Journal of Experimental Medicine 200, 569-580CrossRefGoogle ScholarPubMed
113Velazquez, L. et al. (2002) Cytokine signaling and hematopoietic homeostasis are disrupted in Lnk-deficient mice. Journal of Experimental Medicine 195, 1599-1611CrossRefGoogle ScholarPubMed
114Lasho, T.L., Pardanani, A. and Tefferi, A. (2010) LNK mutations in JAK2 mutation-negative erythrocytosis. New England Journal of Medicine 363, 1189-1190CrossRefGoogle ScholarPubMed
115Oh, S.T. et al. (2010) Novel mutations in the inhibitory adaptor protein LNK drive JAK-STAT signaling in patients with myeloproliferative neoplasms. Blood 116, 988-992CrossRefGoogle ScholarPubMed
116Pardanani, A. et al. (2010) LNK mutation studies in blast-phase myeloproliferative neoplasms, and in chronic-phase disease with TET2, IDH, JAK2 or MPL mutations. Leukemia 24, 1713-1718CrossRefGoogle ScholarPubMed
117Lasho, T.L. et al. (2011) Clonal hierarchy and allelic mutation segregation in a myelofibrosis patient with two distinct LNK mutations. Leukemia 25, 1056-8CrossRefGoogle Scholar
118Rudd, C.E. (2001) Lnk adaptor: novel negative regulator of B cell lymphopoiesis. Sci STKE 2001, pe1 85, 1-3Google Scholar
119Bersenev, A. et al. (2010) Lnk constrains myeloproliferative diseases in mice. Journal of Clinical Investigation 120, 2058-2069CrossRefGoogle ScholarPubMed
120Delhommeau, F. et al. (2009) Mutation in TET2 in myeloid cancers. New England Journal of Medicine 360, 2289-2301CrossRefGoogle ScholarPubMed
121Carbuccia, N. et al. (2009) Mutations of ASXL1 gene in myeloproliferative neoplasms. Leukemia 23, 2183-2186CrossRefGoogle ScholarPubMed
122Green, A. and Beer, P. (2010) Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms. New England Journal of Medicine 362, 369-370CrossRefGoogle ScholarPubMed
123Tefferi, A. et al. (2010) IDH1 and IDH2 mutation studies in 1473 patients with chronic-, fibrotic- or blast-phase essential thrombocythemia, polycythemia vera or myelofibrosis. Leukemia 24, 1302-1309CrossRefGoogle ScholarPubMed
124Grand, F.H. et al. (2009) Frequent CBL mutations associated with 11q acquired uniparental disomy in myeloproliferative neoplasms. Blood 113, 6182-6192CrossRefGoogle ScholarPubMed
125Jager, R. et al. (2010) Deletions of the transcription factor Ikaros in myeloproliferative neoplasms. Leukemia 24, 1290-1298CrossRefGoogle ScholarPubMed
126Ernst, T. et al. (2010) Inactivating mutations of the histone methyltransferase gene EZH2 in myeloid disorders. Nature Genetics 42, 722-726CrossRefGoogle ScholarPubMed
127Tefferi, A. and Vainchenker, W. (2011) Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. Journal of Clinical Oncology 29, 573-582CrossRefGoogle ScholarPubMed
128Verstovsek, S. (2010) Therapeutic potential of Janus-activated kinase-2 inhibitors for the management of myelofibrosis. Clinical Cancer Research 16, 1988-1996CrossRefGoogle ScholarPubMed
129Pardanani, A. et al. (2011) JAK inhibitor therapy for myelofibrosis: critical assessment of value and limitations. Leukemia 25, 218-225CrossRefGoogle Scholar
130Marubayashi, S. et al. (2010) HSP90 is a therapeutic target in JAK2-dependent myeloproliferative neoplasms in mice and humans. Journal of Clinical Investigation 120, 3578-3593CrossRefGoogle ScholarPubMed
131Wang, Y. et al. (2009) Cotreatment with panobinostat and JAK2 inhibitor TG101209 attenuates JAK2V617F levels and signaling and exerts synergistic cytotoxic effects against human myeloproliferative neoplastic cells. Blood 114, 5024-5033CrossRefGoogle ScholarPubMed
132Guglielmelli, P. et al. (2011) Safety and efficacy of everolimus, a mTOR inhibitor, as single agent in a phase 1/2 study in patients with myelofibrosis. Blood 118, 2069-2076CrossRefGoogle Scholar
133Tallman, M.S. et al. (2000) Acute megakaryocytic leukemia: the Eastern Cooperative Oncology Group experience. Blood 96, 2405-2411Google ScholarPubMed
134Pagano, L. et al. (2002) Acute megakaryoblastic leukemia: experience of GIMEMA trials. Leukemia 16, 1622-1626CrossRefGoogle ScholarPubMed
135Barnard, D.R. et al. (2007) Comparison of childhood myelodysplastic syndrome, AML FAB M6 or M7, CCG 2891: report from the Children's Oncology Group. Pediatric Blood and Cancer 49, 17-22CrossRefGoogle ScholarPubMed
136Hasle, H. et al. (2008) Myeloid leukemia in children 4 years or older with Down syndrome often lacks GATA1 mutation and cytogenetics and risk of relapse are more akin to sporadic AML. Leukemia 22, 1428-1430CrossRefGoogle ScholarPubMed
137Langebrake, C., Creutzig, U. and Reinhardt, D. (2005) Immunophenotype of Down syndrome acute myeloid leukemia and transient myeloproliferative disease differs significantly from other diseases with morphologically identical or similar blasts. Klinische Padiatrie 217, 126-134CrossRefGoogle ScholarPubMed
138Creutzig, U. et al. (2005) AML patients with Down syndrome have a high cure rate with AML-BFM therapy with reduced dose intensity. Leukemia 19, 1355-1360CrossRefGoogle ScholarPubMed
139Rao, A. et al. (2006) Treatment for myeloid leukaemia of Down syndrome: population-based experience in the UK and results from the Medical Research Council AML 10 and AML 12 trials. British Journal of Haematology 132, 576-583CrossRefGoogle ScholarPubMed
140Gamis, A.S. et al. (2003) Increased age at diagnosis has a significantly negative effect on outcome in children with Down syndrome and acute myeloid leukemia: a report from the Children's Cancer Group Study 2891. Journal of Clinical Oncology 21, 3415-3422CrossRefGoogle Scholar
141Zwaan, C.M. et al. (2002) Different drug sensitivity profiles of acute myeloid and lymphoblastic leukemia and normal peripheral blood mononuclear cells in children with and without Down syndrome. Blood 99, 245-251CrossRefGoogle ScholarPubMed
142Gamis, A.S. (2005) Acute myeloid leukemia and Down syndrome evolution of modern therapy – -state of the art review. Pediatric Blood and Cancer 44, 13-20CrossRefGoogle ScholarPubMed
143Wickrema, A. and Crispino, J.D. (2007) Erythroid and megakaryocytic transformation. Oncogene 26, 6803-6815CrossRefGoogle ScholarPubMed
144Vyas, P. and Crispino, J.D. (2007) Molecular insights into Down syndrome-associated leukemia. Current Opinion in Pediatrics 19, 9-14CrossRefGoogle ScholarPubMed
145Hollanda, L.M. et al. (2006) An inherited mutation leading to production of only the short isoform of GATA-1 is associated with impaired erythropoiesis. Nature Genetics 38, 807-812CrossRefGoogle ScholarPubMed
146Li, Z. et al. (2005) Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nature Genetics 37, 613-619CrossRefGoogle ScholarPubMed
147Malinge, S., Izraeli, S. and Crispino, J.D. (2009) Insights into the manifestations, outcomes, and mechanisms of leukemogenesis in Down syndrome. Blood 113, 2619-2628CrossRefGoogle ScholarPubMed
148Walters, D.K. et al. (2006) Activating alleles of JAK3 in acute megakaryoblastic leukemia. Cancer Cell 10, 65-75CrossRefGoogle ScholarPubMed
149Kiyoi, H. et al. (2007) JAK3 mutations occur in acute megakaryoblastic leukemia both in Down syndrome children and non-Down syndrome adults. Leukemia 21, 574-576CrossRefGoogle ScholarPubMed
150De Vita, S. et al. (2007) Loss-of-function JAK3 mutations in TMD and AMKL of Down syndrome. British Journal of Haematology 137, 337-341CrossRefGoogle ScholarPubMed
151Sato, T. et al. (2008) Functional analysis of JAK3 mutations in transient myeloproliferative disorder and acute megakaryoblastic leukaemia accompanying Down syndrome. British Journal of Haematology 141, 681-688CrossRefGoogle ScholarPubMed
152Cornejo, M.G., Boggon, T.J. and Mercher, T. (2009) JAK3: a two-faced player in hematological disorders. International Journal of Biochemistry and Cell Biology 41, 2376-2379CrossRefGoogle ScholarPubMed
153Radtke, I. et al. (2009) Genomic analysis reveals few genetic alterations in pediatric acute myeloid leukemia. Proceedings of the National Academy of Sciences of the United States of America 106, 12944-12949CrossRefGoogle ScholarPubMed
154Leow, S. et al. (2011) FLT3 mutation and expression did not adversely affect clinical outcome of childhood acute leukaemia-a study of 531 Southeast Asian children by the Ma-Spore study group. Hematological Oncology doi: 10.1002/hon.987. [Epub ahead of print]CrossRefGoogle Scholar
155Klusmann, J.H. et al. (2010) Developmental stage-specific interplay of GATA1 and IGF signaling in fetal megakaryopoiesis and leukemogenesis. Genes and Development 24, 1659-1672CrossRefGoogle ScholarPubMed
156Ge, Y. et al. (2006) Differential gene expression, GATA1 target genes, and the chemotherapy sensitivity of Down syndrome megakaryocytic leukemia. Blood 107, 1570-1581CrossRefGoogle ScholarPubMed
157Bourquin, J.P. et al. (2006) Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. Proceedings of the National Academy of Sciences of the United States of America 103, 3339-3344CrossRefGoogle ScholarPubMed
158Carroll, A. 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, 748-752CrossRefGoogle Scholar
159Bernstein, J. 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, 216-218CrossRefGoogle Scholar
160Rubnitz, J.E. et al. (2007) Prognostic factors and outcome of recurrence in childhood acute myeloid leukemia. Cancer 109, 157-163CrossRefGoogle ScholarPubMed
161Mercher, T. 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. Proceedings of the National Academy of Sciences of the United States of America 98, 5776-5779CrossRefGoogle Scholar
162Miralles, F. et al. (2003) Actin dynamics control SRF activity by regulation of its coactivator MAL. Cell 113, 329-342CrossRefGoogle ScholarPubMed
163Descot, A. et al. (2008) OTT-MAL is a deregulated activator of serum response factor-dependent gene expression. Molecular and Cellular Biology 28, 6171-6181CrossRefGoogle ScholarPubMed
164Ariyoshi, M. and Schwabe, J.W. (2003) A conserved structural motif reveals the essential transcriptional repression function of Spen proteins and their role in developmental signaling. Genes and Development 17, 1909-1920CrossRefGoogle ScholarPubMed
165Oswald, F. et al. (2002) SHARP is a novel component of the Notch/RBP-Jkappa signalling pathway. EMBO Journal 21, 5417-5426CrossRefGoogle ScholarPubMed
166Ma, X. et al. (2007) Rbm15 modulates notch-induced transcriptional activation and affects myeloid differentiation. Molecular and Cellular Biology 27, 3056-3064CrossRefGoogle ScholarPubMed
167Mercher, T. et al. (2009) The OTT-MAL fusion oncogene activates RBPJ-mediated transcription and induces acute megakaryoblastic leukemia in a knock-in mouse model. Journal of Clinical Investigation 119, 852-864Google Scholar
168Abdelhaleem, M. et al. (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, 352-353CrossRefGoogle ScholarPubMed
169Oki, Y. et al. (2006) Adult acute megakaryocytic leukemia: an analysis of 37 patients treated at M.D. Anderson Cancer Center. Blood 107, 880-884CrossRefGoogle ScholarPubMed

Further reading, resources and contacts

The following recent papers may be of interest to those who want to delve deeper into recent reports of normal and malignant megakaryopoiesis:

Tefferi, A. and Vainchenker, W. (2011) Myeloproliferative neoplasms: molecular pathophysiology, essential clinical understanding, and treatment strategies. Journal of Clinical Oncology 29, 573-582CrossRefGoogle ScholarPubMed
Verstovsek, S. (2010) Therapeutic potential of Janus-activated kinase-2 inhibitors for the management of myelofibrosis. Clinical Cancer Research 16, 1988-1996CrossRefGoogle ScholarPubMed
Pardanani, A. et al. (2011) JAK inhibitor therapy for myelofibrosis: critical assessment of value and limitations. Leukemia 25, 218-225CrossRefGoogle Scholar
Chen, E. et al. (2010) Distinct clinical phenotypes associated with JAK2V617F reflect differential STAT1 signaling. Cancer Cell 18, 524-535CrossRefGoogle ScholarPubMed
Chagraoui, H. et al. (2011) SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis. Blood 118, 723-735.CrossRefGoogle ScholarPubMed
Doré, L. and Crispino, J.D. (2011) Transcription factor networks in erythroid cell and megakaryocyte development. Blood 118, 231-239CrossRefGoogle ScholarPubMed