The KDM3A–KLF2–IRF4 axis maintains myeloma cell survival

Hiroto Ohguchi, Teru Hideshima, Manoj K. Bhasin, Gullu T. Gorgun, Loredana Santo, Michele Cea, Mehmet K. Samur, Naoya Mimura, Rikio Suzuki, Yu-Tzu Tai, Ruben D. Carrasco, Noopur Raje, Paul G. Richardson, Nikhil C. Munshi, Hideo Harigae, Takaomi Sanda, Juro Sakai and Kenneth C. Anderson ()
Additional contact information
Hiroto Ohguchi: Dana-Farber Cancer Institute
Teru Hideshima: Dana-Farber Cancer Institute
Manoj K. Bhasin: BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center
Gullu T. Gorgun: Dana-Farber Cancer Institute
Loredana Santo: MGH Cancer Center, Massachusetts General Hospital
Michele Cea: Dana-Farber Cancer Institute
Mehmet K. Samur: Dana-Farber Cancer Institute
Naoya Mimura: Dana-Farber Cancer Institute
Rikio Suzuki: Dana-Farber Cancer Institute
Yu-Tzu Tai: Dana-Farber Cancer Institute
Ruben D. Carrasco: Dana-Farber Cancer Institute
Noopur Raje: MGH Cancer Center, Massachusetts General Hospital
Paul G. Richardson: Dana-Farber Cancer Institute
Nikhil C. Munshi: Dana-Farber Cancer Institute
Hideo Harigae: Tohoku University Graduate School of Medicine
Takaomi Sanda: Cancer Science Institute of Singapore, National University of Singapore
Juro Sakai: Research Center for Advanced Science and Technology, University of Tokyo
Kenneth C. Anderson: Dana-Farber Cancer Institute

Nature Communications, 2016, vol. 7, issue 1, 1-15

Abstract: Abstract KDM3A is implicated in tumorigenesis; however, its biological role in multiple myeloma (MM) has not been elucidated. Here we identify KDM3A–KLF2–IRF4 axis dependence in MM. Knockdown of KDM3A is toxic to MM cells in vitro and in vivo. KDM3A maintains expression of KLF2 and IRF4 through H3K9 demethylation, and knockdown of KLF2 triggers apoptosis. Moreover, KLF2 directly activates IRF4 and IRF4 reciprocally upregulates KLF2, forming a positive autoregulatory circuit. The interaction of MM cells with bone marrow milieu mediates survival of MM cells. Importantly, silencing of KDM3A, KLF2 or IRF4 both decreases MM cell adhesion to bone marrow stromal cells and reduces MM cell homing to the bone marrow, in association with decreased ITGB7 expression in MAF-translocated MM cell lines. Our results indicate that the KDM3A–KLF2–IRF4 pathway plays an essential role in MM cell survival and homing to the bone marrow, and therefore represents a therapeutic target.

Date: 2016
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DOI: 10.1038/ncomms10258

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