title: 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.
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore.
authors: Chelsia Qiuxia
authors: CQ
authors: Wang
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
authors: Vaidehi
authors: V
authors: Krishnan
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
authors: Lavina Sierra
authors: LS
authors: Tay
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
authors: Desmond Wai Loon
authors: DW
authors: Chin
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
authors: Cai Ping
authors: CP
authors: Koh
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
authors: Jing Yuan
authors: JY
authors: Chooi
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore.
authors: Giselle Sek Suan
authors: GS
authors: Nah
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
authors: Linsen
authors: L
authors: Du
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
authors: Bindya
authors: B
authors: Jacob
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
authors: Namiko
authors: N
authors: Yamashita
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
authors: Soak Kuan
authors: SK
authors: Lai
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
authors: Tuan Zea
authors: TZ
authors: Tan
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore.
authors: Seiichi
authors: S
authors: Mori
authors: Laboratory for Transcriptional Regulation, RIKEN Center for Integrative Medical Sciences, Yokohama, Kanagawa 230-0045, Japan.
authors: Ichiro
authors: I
authors: Tanuichi
authors: Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore. Electronic address: vinayt@imcb.a-star.edu.sg.
authors: Vinay
authors: V
authors: Tergaonkar
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore. Electronic address: csiitoy@nus.edu.sg.
authors: Yoshiaki
authors: Y
authors: Ito
authors: Cancer Science Institute of Singapore, National University of Singapore, Singapore 117599, Singapore; Institute of Molecular and Cell Biology, A(∗)STAR, Singapore 138673, Singapore; Institute of Bioengineering and Nanotechnology, A(∗)STAR, Singapore 138669, Singapore. Electronic address: csimo@nus.edu.sg.
authors: Motomi
authors: M
authors: Osato
mesh_terms: D000818:Animals; D001853:Bone Marrow / Q000378:metabolism* / Q000473:pathology; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics* / Q000378:metabolism; D050677:Core Binding Factor Alpha 3 Subunit / Q000235:genetics* / Q000378:metabolism; D004260:DNA Repair; D005199:Fanconi Anemia / Q000235:genetics* / Q000378:metabolism; D052236:Fanconi Anemia Complementation Group D2 Protein / Q000378:metabolism; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D045325:HCT116 Cells; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007938:Leukemia / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D050677:Core Binding Factor Alpha 3 Subunit; C499904:Fancd2 protein, mouse; D052236:Fanconi Anemia Complementation Group D2 Protein; C493726:Runx1 protein, mouse; C493730:Runx3 protein, mouse