RUNX1 haploinsufficiency results in granulocyte colony-stimulating factor hypersensitivity

D. W L Chin, M. Sakurai, G. S S Nah, L. Du, B. Jacob, T. Yokomizo, T. Matsumura, T. Suda, G. Huang, X. Y. Fu, Y. Ito, Hideaki Nakajima, M. Osato

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11 Citations (Scopus)

Abstract

RUNX1/AML1 is among the most commonly mutated genes in human leukemia. Haploinsufficiency of RUNX1 causes familial platelet disorder with predisposition to myeloid malignancies (FPD/MM). However, the molecular mechanism of FPD/MM remains unknown. Here we show that murine Runx1+/- hematopoietic cells are hypersensitive to granulocyte colony-stimulating factor (G-CSF), leading to enhanced expansion and mobilization of stem/progenitor cells and myeloid differentiation block. Upon G-CSF stimulation, Runx1+/- cells exhibited a more pronounced phosphorylation of STAT3 as compared with Runx1+/+ cells, which may be due to reduced expression of Pias3, a key negative regulator of STAT3 signaling, and reduced physical sequestration of STAT3 by RUNX1. Most importantly, blood cells from a FPD patient with RUNX1 mutation exhibited similar G-CSF hypersensitivity. Taken together, Runx1 haploinsufficiency appears to predispose FPD patients to MM by expanding the pool of stem/progenitor cells and blocking myeloid differentiation in response to G-CSF.

Original languageEnglish
Article numbere379
JournalBlood Cancer Journal
Volume6
DOIs
Publication statusPublished - 2016 Jan 8

ASJC Scopus subject areas

  • Oncology
  • Hematology

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    Chin, D. W. L., Sakurai, M., Nah, G. S. S., Du, L., Jacob, B., Yokomizo, T., Matsumura, T., Suda, T., Huang, G., Fu, X. Y., Ito, Y., Nakajima, H., & Osato, M. (2016). RUNX1 haploinsufficiency results in granulocyte colony-stimulating factor hypersensitivity. Blood Cancer Journal, 6, [e379]. https://doi.org/10.1038/bcj.2015.105