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; H Nakajima; M Osato

doi:10.1038/bcj.2015.105

RUNX1 haploinsufficiency results in granulocyte colony-stimulating factor hypersensitivity

Blood Cancer J. 2016 Jan 8;6(1):e379. doi: 10.1038/bcj.2015.105.

Authors

D W L Chin¹, M Sakurai², G S S Nah¹, L Du¹, B Jacob³, T Yokomizo^{1

4}, T Matsumura¹, T Suda^{1

4}, G Huang⁵, X-Y Fu^{1

6}, Y Ito^{1

3}, H Nakajima², M Osato^{1

4

7

8}

Affiliations

¹ Cancer Science Institute of Singapore, National University of Singapore, Singapore.
² Division of Hematology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.
³ Institute of Molecular and Cell Biology, A*STAR, Singapore.
⁴ International Research Center for Medical Sciences, Kumamoto University, Kumamato, Japan.
⁵ Department of Paediatrics, Cincinnati Children's Hospital, Cincinnati, OH, USA.
⁶ Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
⁷ Institute of Bioengineering and Nanotechnology, A*STAR, Singapore.
⁸ Department of Paediatrics, National University of Singapore, Singapore.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Blood Platelet Disorders / genetics
Bone Marrow Cells / drug effects
Bone Marrow Cells / metabolism
Core Binding Factor Alpha 2 Subunit / genetics*
Cytokines / pharmacology
Disease Models, Animal
Drug Resistance / genetics*
Gene Expression Regulation, Leukemic / drug effects
Genetic Predisposition to Disease*
Genotype
Granulocyte Colony-Stimulating Factor / administration & dosage
Granulocyte Colony-Stimulating Factor / pharmacology*
Haploinsufficiency*
Hematopoietic Stem Cells / drug effects
Hematopoietic Stem Cells / metabolism
Humans
Leukemia, Myeloid, Acute / genetics*
Leukemia, Myeloid, Acute / pathology
Mice
Molecular Chaperones / genetics
Molecular Chaperones / metabolism
Mutation
Phosphorylation
Protein Binding
Protein Inhibitors of Activated STAT / genetics
Protein Inhibitors of Activated STAT / metabolism
Receptors, CXCR4 / genetics
Receptors, CXCR4 / metabolism
STAT3 Transcription Factor / metabolism
Signal Transduction / drug effects

Substances

Core Binding Factor Alpha 2 Subunit
Cytokines
Molecular Chaperones
PIAS3 protein, human
Protein Inhibitors of Activated STAT
Receptors, CXCR4
STAT3 Transcription Factor
Granulocyte Colony-Stimulating Factor