TY - JOUR
T1 - RUNX1 haploinsufficiency results in granulocyte colony-stimulating factor hypersensitivity
AU - Chin, D. W.L.
AU - Sakurai, M.
AU - Nah, G. S.S.
AU - Du, L.
AU - Jacob, B.
AU - Yokomizo, T.
AU - Matsumura, T.
AU - Suda, T.
AU - Huang, G.
AU - Fu, X. Y.
AU - Ito, Y.
AU - Nakajima, H.
AU - Osato, M.
N1 - Funding Information:
We thank CSI FACS facility for their technical assistance; members of M.O. laboratory for helpful discussion; MD2 Vivarium, NUS for mouse husbandry; W. Krek for CXCR4 promoter luciferase construct. This work was supported by National Medical Research Council, the National Research Foundation Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative, Biomedical Research Council, and A*STAR (Agency of Science Technology and Research).
Publisher Copyright:
© 2016, Nature Publishing Group. All rights reserved.
PY - 2016/1/8
Y1 - 2016/1/8
N2 - 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.
AB - 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.
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U2 - 10.1038/bcj.2015.105
DO - 10.1038/bcj.2015.105
M3 - Article
C2 - 26745853
AN - SCOPUS:84953775209
SN - 2044-5385
VL - 6
JO - Blood Cancer Journal
JF - Blood Cancer Journal
M1 - e379
ER -