RUNX1 haploinsufficiency results in granulocyte colony-stimulating factor hypersensitivity.

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

doi: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.

Highlights

RUNX1 is one of the most frequently mutated genes in human leukemia
A germline mutation of RUNX1 is causally linked to familial platelet disorder with predisposition to myeloid malignancies (FPD/MM), a rare autosomal dominant disorder characterized by modest thrombocytopenia and defective platelet function, with 35% lifetime risk of developing leukemia.[3,4,5,6]
To investigate the impact of RUNX1 haploinsufficiency on hematopoiesis and leukemogenesis in FPD/MM patients, we used tion was accompanied by a minor increase in the frequency of CD34+Flt3-KSL short-term hematopoietic stem cells (HSCs)

Summary

Introduction

RUNX1 is one of the most frequently mutated genes in human leukemia. Approximately 30% of acute leukemias carry RUNX1 genetic alterations such as chromosomal translocation, point mutations and deletions.[1,2] A germline mutation of RUNX1 is causally linked to familial platelet disorder with predisposition to myeloid malignancies (FPD/MM), a rare autosomal dominant disorder characterized by modest thrombocytopenia and defective platelet function, with 35% lifetime risk of developing leukemia.[3,4,5,6] To date, ~ 30 families have been reported.[7]. The spleen of Runx1+/ − mice showed increased granulocytes but decreased T-cell frequencies (Supplementary Figure 1C). The colony-forming capacity of the KSL compartment of Runx1+/ − mice showed the greatest difference when compared with littermate control, though this trend of G-CSF hypersensitivity was observed in other myeloid progenitor compartments (Figure 1c).

Results

Conclusion