Gene expression profiles of murine Runx1;Runx3 double deficient cKit+Sca1+Lin- hematopoietic stem/progenitor cells

The RUNX genes encode for 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 like 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 independent of CBF, suggesting non-transcriptional role for RUNX in DNA repair. These findings suggest that RUNX dysfunction causes DNA repair defect, besides transcriptional misregulation, and promotes development of leukemias and other cancers.

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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