Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients

Masatoshi Sakurai, H. Kunimoto, N. Watanabe, Y. Fukuchi, Shinsuke Yuasa, S. Yamazaki, T. Nishimura, K. Sadahira, Keiichi Fukuda, Hideyuki Okano, H. Nakauchi, Y. Morita, I. Matsumura, K. Kudo, E. Ito, Y. Ebihara, K. Tsuji, Y. Harada, H. Harada, Shinichiro OkamotoH. Nakajima

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Abstract

Somatic mutation of RUNX1 is implicated in various hematological malignancies, including myelodysplastic syndrome and acute myeloid leukemia (AML), and previous studies using mouse models disclosed its critical roles in hematopoiesis. However, the role of RUNX1 in human hematopoiesis has never been tested in experimental settings. Familial platelet disorder (FPD)/AML is an autosomal dominant disorder caused by germline mutation of RUNX1, marked by thrombocytopenia and propensity to acute leukemia. To investigate the physiological function of RUNX1 in human hematopoiesis and pathophysiology of FPD/AML, we derived induced pluripotent stem cells (iPSCs) from three distinct FPD/AML pedigrees (FPD-iPSCs) and examined their defects in hematopoietic differentiation. By in vitro differentiation assays, FPD-iPSCs were clearly defective in the emergence of hematopoietic progenitors and differentiation of megakaryocytes, and overexpression of wild-type (WT)-RUNX1 reversed most of these phenotypes. We further demonstrated that overexpression of mutant-RUNX1 in WT-iPSCs did not recapitulate the phenotype of FPD-iPSCs, showing that the mutations were of loss-of-function type. Taken together, this study demonstrated that haploinsufficient RUNX1 allele imposed cell-intrinsic defects on hematopoietic differentiation in human experimental settings and revealed differential impacts of RUNX1 dosage on human and murine megakaryopoiesis. FPD-iPSCs will be a useful tool to investigate mutant RUNX1-mediated molecular processes in hematopoiesis and leukemogenesis.

Original languageEnglish
Pages (from-to)2344-2354
Number of pages11
JournalLeukemia
Volume28
Issue number12
DOIs
Publication statusPublished - 2014 Dec 11

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Induced Pluripotent Stem Cells
Acute Myeloid Leukemia
Blood Platelets
Hematopoiesis
Megakaryocyte Progenitor Cells
Phenotype
Mutation
Germ-Line Mutation
Myelodysplastic Syndromes
Hematologic Neoplasms
Pedigree
Thrombocytopenia
Leukemia
Alleles

ASJC Scopus subject areas

  • Hematology
  • Cancer Research
  • Anesthesiology and Pain Medicine
  • Medicine(all)

Cite this

Sakurai, M., Kunimoto, H., Watanabe, N., Fukuchi, Y., Yuasa, S., Yamazaki, S., ... Nakajima, H. (2014). Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients. Leukemia, 28(12), 2344-2354. https://doi.org/10.1038/leu.2014.136

Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients. / Sakurai, Masatoshi; Kunimoto, H.; Watanabe, N.; Fukuchi, Y.; Yuasa, Shinsuke; Yamazaki, S.; Nishimura, T.; Sadahira, K.; Fukuda, Keiichi; Okano, Hideyuki; Nakauchi, H.; Morita, Y.; Matsumura, I.; Kudo, K.; Ito, E.; Ebihara, Y.; Tsuji, K.; Harada, Y.; Harada, H.; Okamoto, Shinichiro; Nakajima, H.

In: Leukemia, Vol. 28, No. 12, 11.12.2014, p. 2344-2354.

Research output: Contribution to journalArticle

Sakurai, M, Kunimoto, H, Watanabe, N, Fukuchi, Y, Yuasa, S, Yamazaki, S, Nishimura, T, Sadahira, K, Fukuda, K, Okano, H, Nakauchi, H, Morita, Y, Matsumura, I, Kudo, K, Ito, E, Ebihara, Y, Tsuji, K, Harada, Y, Harada, H, Okamoto, S & Nakajima, H 2014, 'Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients', Leukemia, vol. 28, no. 12, pp. 2344-2354. https://doi.org/10.1038/leu.2014.136
Sakurai, Masatoshi ; Kunimoto, H. ; Watanabe, N. ; Fukuchi, Y. ; Yuasa, Shinsuke ; Yamazaki, S. ; Nishimura, T. ; Sadahira, K. ; Fukuda, Keiichi ; Okano, Hideyuki ; Nakauchi, H. ; Morita, Y. ; Matsumura, I. ; Kudo, K. ; Ito, E. ; Ebihara, Y. ; Tsuji, K. ; Harada, Y. ; Harada, H. ; Okamoto, Shinichiro ; Nakajima, H. / Impaired hematopoietic differentiation of RUNX1-mutated induced pluripotent stem cells derived from FPD/AML patients. In: Leukemia. 2014 ; Vol. 28, No. 12. pp. 2344-2354.
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AU - Matsumura, I.

AU - Kudo, K.

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AU - Ebihara, Y.

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AU - Okamoto, Shinichiro

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