9. O’Brien MM, Taub JW, Chang MN, Massey GV, Stine KC, et al. (2008) Cardiomyopathy in children with Down syndrome treated for acute myeloid leukemia: a report from the Children’s Oncology Group Study POG 9421. J Clin Oncol 26: 414–420. 10. Harigae H, Xu G, Sugawara T, Ishikawa I, Toki T, et al. (2004) The GATA1 mutation in an adult patient with acute megakaryoblastic leukemia not accompanying Down syndrome. Blood 103: 3242–3243. 11. Inaba H, Londero M, Maurer SH, Onciu M, Ge Y, et al. (2011) Acute Megakaryoblastic Leukemia Without GATA1 Mutation After Transient Myeloproliferative Disorder in an Infant Without Down Syndrome. J Clin Oncol 29: e230–e233. 12. Wechsler J, Greene M, McDevitt MA, Anastasi J, Karp JE, et al. (2002) Acquired mutations in GATA1 in the megakaryoblastic leukemia of Down syndrome. Nat Genet 32: 148–152. 13. Crispino JD (2005) GATA1 in normal and malignant hematopoiesis. Semin Cell Dev Biol 16: 137–147. 14. Li Z, Godinho FJ, Klusmann JH, Garriga-Canut M, Yu C, et al. (2005) Developmental stage-selective effect of somatically mutated leukemogenic transcription factor GATA1. Nat Genet 37: 613–619. 15. Shimamoto T, Ohyashiki K, Ohyashiki JH, Kawakubo K, Fujimura T, et al. (1995) The expression pattern of erythrocyte/megakaryocyte-related transcrip- tion factors GATA-1 and the stem cell leukemia gene correlates with hematopoietic differentiation and is associated with outcome of acute myeloid leukemia. Blood 86: 3173–3180. 16. Ge Y, Stout ML, Tatman DA, Jensen TL, Buck S, et al. (2005) GATA1, cytidine deaminase, and the high cure rate of Down syndrome children with acute megakaryocytic leukemia. J Natl Cancer Inst 97: 226–231. 17. Sato T, Fuse A, Eguchi M, Hayashi Y, Ryo R, et al. (1989) Establishment of a human leukaemic cell line (CMK) with megakaryocytic characteristics from a Down’s syndrome patient with acute megakaryoblastic leukaemia. Br J Haematol 72: 184–190. 18. Edwards H, Xie C, LaFiura KM, Dombkowski AA, Buck SA, et al. (2009) RUNX1 regulates phosphoinositide 3-kinase/AKT pathway: role in chemo- therapy sensitivity in acute megakaryocytic leukemia. Blood 114: 2744–2752. 19. Xie C, Edwards H, Xu X, Zhou H, Buck SA, et al. (2010) Mechanisms of synergistic antileukemic interactions between valproic acid and cytarabine in pediatric acute myeloid leukemia. Clin Cancer Res 16: 5499–5510. 20. Ge Y, LaFiura KM, Dombkowski AA, Chen Q, Payton SG, et al. (2008) The role of the proto-oncogene ETS2 in acute megakaryocytic leukemia biology and therapy. Leukemia 22: 521–529. 21. Rajagopalan D (2003) A comparison of statistical methods for analysis of high density oligonucleotide array data. Bioinformatics 19: 1469–1476. 22. Ge Y, Dombkowski AA, LaFiura KM, Tatman D, Yedidi RS, et al. (2006) Differential gene expression, GATA1 target genes, and the chemotherapy sensitivity of Down syndrome megakaryocytic leukemia. Blood 107: 1570–1581. 23. Liu M, Ge Y, Payton SG, Aboukameel A, Buck S, et al. (2006) Transcriptional regulation of the human reduced folate carrier in childhood acute lymphoblastic leukemia cells. Clin Cancer Res 12: 608–616. 24. Ge Y, Jensen TL, Matherly LH, Taub JW (2003) Transcriptional regulation of the cystathionine-beta -synthase gene in Down syndrome and non-Down syndrome megakaryocytic leukemia cell lines. Blood 101: 1551–1557. The Role of GATA1s in DS AMkL 25. Takahashi T, Tsuyuoka R, Ueda Y, Suzuki A, Ichiba S, et al. (1991) Megakaryocyte potentiating activity of IL-1, IL-6 and GM-CSF as evaluated by their action on in vitro human megakaryocytic colonies. Br J Haematol 78: 480–487. 26. Visvader JE, Crossley M, Hill J, Orkin SH, Adams JM (1995) The C-terminal zinc finger of GATA-1 or GATA-2 is sufficient to induce megakaryocytic differentiation of an early myeloid cell line. Mol Cell Biol 15: 634–641. 27. 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. 28. Gutierrez L, Tsukamoto S, Suzuki M, Yamamoto-Mukai H, Yamamoto M, et al. (2008) Ablation of Gata1 in adult mice results in aplastic crisis, revealing its essential role in steady-state and stress erythropoiesis. Blood 111: 4375–4385. 29. Fujiwara Y, Browne CP, Cunniff K, Goff SC, Orkin SH (1996) Arrested development of embryonic red cell precursors in mouse embryos lacking transcription factor GATA-1. Proc Natl Acad Sci U S A 93: 12355–12358. 30. Mundschau G, Gurbuxani S, Gamis AS, Greene ME, Arceci RJ, et al. (2003) Mutagenesis of GATA1 is an initiating event in Down syndrome leukemogen- esis. Blood 101: 4298–4300. 31. Hitzler JK, Cheung J, Li Y, Scherer SW, Zipursky A (2003) GATA1 mutations in transient leukemia and acute megakaryoblastic leukemia of Down syndrome. Blood 101: 4301–4304. 32. Rainis L, Bercovich D, Strehl S, Teigler-Schlegel A, Stark B, et al. (2003) Mutations in exon 2 of GATA1 are early events in megakaryocytic malignancies associated with trisomy 21. Blood 102: 981–986. 33. Tunstall-Pedoe O, Roy A, Karadimitris A, de la Fuente J, Fisk NM, et al. (2008) Abnormalities in the myeloid progenitor compartment in Down syndrome fetal liver precede acquisition of GATA1 mutations. Blood 112: 4507–4511. 34. Chou ST, Opalinska JB, Yao Y, Fernandes MA, Kalota A, et al. (2008) Trisomy 21 enhances human fetal erythro-megakaryocytic development. Blood 112: 4503–4506. 35. Taub JW, Mundschau G, Ge Y, Poulik JM, Qureshi F, et al. (2004) Prenatal origin of GATA1 mutations may be an initiating step in the development of megakaryocytic leukemia in Down syndrome. Blood 104: 1588–1589. 36. Bourquin JP, Subramanian A, Langebrake C, Reinhardt D, Bernard O, et al. (2006) Identification of distinct molecular phenotypes in acute megakaryoblastic leukemia by gene expression profiling. Proc Natl Acad Sci U S A 103: 3339–3344. 37. Su RJ, Li K, Zhang XB, Pan Yuen PM, Li CK, et al. (2005) Platelet-derived growth factor enhances expansion of umbilical cord blood CD34+ cells in contact with hematopoietic stroma. Stem Cells Dev 14: 223–230. 38. Taub JW, Matherly LH, Stout ML, Buck SA, Gurney JG, et al. (1996) Enhanced metabolism of 1-beta-D-arabinofuranosylcytosine in Down syndrome cells: a contributing factor to the superior event free survival of Down syndrome children with acute myeloid leukemia. Blood 87: 3395–3403. 39. Loew TM, Gamis A, Smith FO, Massey GV, Woods WG, et al. (2004) Down syndrome patients with relapsed acute myelogenous leukemia. Blood 104: Abstract 4526. 40. Kanezaki R, Toki T, Terui K, Xu G, Wang R, et al. (2010) Down syndrome and GATA1 mutations in transient abnormal myeloproliferative disorder: mutation classes correlate with progression to myeloid leukemia. Blood 116: 4631–4638. PLoS ONE | www.plosone.org 10 November 2011 | Volume 6 | Issue 11 | e27486