@article{af18cee1b6704d6d939d5b5c2a137f4c,
title = "The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival",
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.",
author = "Hiroto Ohguchi and Teru Hideshima and Bhasin, {Manoj K.} and Gorgun, {Gullu T.} and Loredana Santo and Michele Cea and Samur, {Mehmet K.} and Naoya Mimura and Rikio Suzuki and Tai, {Yu Tzu} and Carrasco, {Ruben D.} and Noopur Raje and Richardson, {Paul G.} and Munshi, {Nikhil C.} and Hideo Harigae and Takaomi Sanda and Juro Sakai and Anderson, {Kenneth C.}",
note = "Funding Information: We thank Dr James E. Bradner for helpful suggestions and discussions, Dr Takashi Minami for providing the KLF2 antibody (N2212), Drs Bjoern Chapuy and Margaret A. Shipp for providing HBL-1 and SU-DHL4 cell lines and Dr Shinsuke Iida for providing KIS-1 cell line. This research was supported by NIH grants SPORE P50 100707 (N.C.M. and K.C.A.), PO-1 78378 (N.C.M. and K.C.A.), PO-1 155258 (M.K.S., N.C.M., and K.C.A.), and RO-1 50947 (K.C.A.). K.C.A. is an American Cancer Society Clinical Research Professor. H.O. was supported in part by a fellowship from the Uehara Memorial Foundation. Publisher Copyright: {\textcopyright} 2016, Nature Publishing Group. All rights reserved.",
year = "2016",
month = jan,
day = "5",
doi = "10.1038/ncomms10258",
language = "English",
volume = "7",
journal = "Nature Communications",
issn = "2041-1723",
publisher = "Nature Publishing Group",
}