Please use this identifier to cite or link to this item: https://doi.org/10.1038/bcj.2015.105
Title: RUNX1 haploinsufficiency results in granulocyte colony-stimulating factor hypersensitivity
Authors: 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 
Keywords: granulocyte colony stimulating factor
granulocyte macrophage colony stimulating factor
interleukin 3
interleukin 6
protein Pias3
regulator protein
STAT3 protein
transcription factor RUNX1
unclassified drug
chaperone
chemokine receptor CXCR4
cytokine
granulocyte colony stimulating factor
PIAS3 protein, human
protein binding
protein inhibitor of activated STAT
STAT3 protein
transcription factor RUNX1
animal cell
animal experiment
Article
bone marrow cell
cell differentiation
controlled study
haploinsufficiency
hematopoiesis
hematopoietic cell
human
human cell
in vitro study
leukemogenesis
mouse
nonhuman
point mutation
protein expression
protein phosphorylation
protein protein interaction
signal transduction
stem cell expansion
stem cell mobilization
thrombocyte disorder
acute myeloid leukemia
animal
disease model
drug effects
drug resistance
gene expression regulation
genetic predisposition
genetics
genotype
hematopoietic stem cell
metabolism
mutation
pathology
phosphorylation
Animals
Blood Platelet Disorders
Bone Marrow Cells
Core Binding Factor Alpha 2 Subunit
Cytokines
Disease Models, Animal
Drug Resistance
Gene Expression Regulation, Leukemic
Genetic Predisposition to Disease
Genotype
Granulocyte Colony-Stimulating Factor
Haploinsufficiency
Hematopoietic Stem Cells
Humans
Leukemia, Myeloid, Acute
Mice
Molecular Chaperones
Mutation
Phosphorylation
Protein Binding
Protein Inhibitors of Activated STAT
Receptors, CXCR4
Signal Transduction
STAT3 Transcription Factor
Issue Date: 2016
Publisher: Nature Publishing Group
Citation: 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. ScholarBank@NUS Repository. https://doi.org/10.1038/bcj.2015.105
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. © 2016, Nature Publishing Group. All rights reserved.
Source Title: Blood Cancer Journal
URI: https://scholarbank.nus.edu.sg/handle/10635/175447
ISSN: 20445385
DOI: 10.1038/bcj.2015.105
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