Disruption of Runx1 and Runx3 leads to bone marrow failure and leukemia predisposition due to transcriptional and DNA repair defects.

Abstract:

:The RUNX genes encode transcription factors involved in development and human disease. RUNX1 and RUNX3 are frequently associated with leukemias, yet the basis for their involvement in leukemogenesis is not fully understood. Here, we show that Runx1;Runx3 double-knockout (DKO) mice exhibited lethal phenotypes due to bone marrow failure and myeloproliferative disorder. These contradictory clinical manifestations are reminiscent of human inherited bone marrow failure syndromes such as Fanconi anemia (FA), caused by defective DNA repair. Indeed, Runx1;Runx3 DKO cells showed mitomycin C hypersensitivity, due to impairment of monoubiquitinated-FANCD2 recruitment to DNA damage foci, although FANCD2 monoubiquitination in the FA pathway was unaffected. RUNX1 and RUNX3 interact with FANCD2 independently of CBFβ, suggesting a nontranscriptional role for RUNX in DNA repair. These findings suggest that RUNX dysfunction causes DNA repair defect, besides transcriptional misregulation, and promotes the development of leukemias and other cancers.

journal_name

Cell Rep

journal_title

Cell reports

authors

Wang CQ,Krishnan V,Tay LS,Chin DW,Koh CP,Chooi JY,Nah GS,Du L,Jacob B,Yamashita N,Lai SK,Tan TZ,Mori S,Tanuichi I,Tergaonkar V,Ito Y,Osato M

doi

10.1016/j.celrep.2014.06.046

subject

Has Abstract

pub_date

2014-08-07 00:00:00

pages

767-82

issue

3

issn

2211-1247

pii

S2211-1247(14)00530-0

journal_volume

8

pub_type

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