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: Chelsia Qiuxia Wang, Vaidehi Krishnan, Lavina Sierra Tay, Desmond Wai Loon Chin, Cai Ping Koh, Jing Yuan Chooi, Giselle Sek Suan Nah, Linsen Du, Bindya Jacob, Namiko Yamashita, Soak Kuan Lai, Tuan Zea Tan, Seiichi Mori, Ichiro Tanuichi, Vinay Tergaonkar, Yoshiaki Ito, Motomi Osato
• Journal: Cell reports (Cell Rep) Vol. 8 Issue 3 Pg. 767-82 (Aug 07 2014) ISSN: 2211-1247 [Electronic] United States
• PMID: 25066130 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Core Binding Factor Alpha 2 Subunit
• Core Binding Factor Alpha 3 Subunit
• Fancd2 protein, mouse
• Fanconi Anemia Complementation Group D2 Protein
• Runx1 protein, mouse
• Runx3 protein, mouse

Topics

• Animals
• Bone Marrow (metabolism, pathology)
• Core Binding Factor Alpha 2 Subunit (genetics, metabolism)
• Core Binding Factor Alpha 3 Subunit (genetics, metabolism)
• DNA Repair
• Fanconi Anemia (genetics, metabolism)
• Fanconi Anemia Complementation Group D2 Protein (metabolism)
• Gene Deletion
• Genetic Predisposition to Disease
• HCT116 Cells
• HEK293 Cells
• HeLa Cells
• Humans
• Leukemia (genetics, metabolism)
• Mice
• Mice, Inbred C57BL