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.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Hiroto
authors.initials: H
authors.lastname: Ohguchi
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Teru
authors.initials: T
authors.lastname: Hideshima
authors.affiliation: BIDMC Genomics, Proteomics, Bioinformatics and Systems Biology Center, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115, USA.
authors.forename: Manoj K
authors.initials: MK
authors.lastname: Bhasin
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Gullu T
authors.initials: GT
authors.lastname: Gorgun
authors.affiliation: MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Loredana
authors.initials: L
authors.lastname: Santo
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Michele
authors.identifier: http://orcid.org/0000-0003-3345-0799
authors.initials: M
authors.lastname: Cea
authors.affiliation: Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Mehmet K
authors.initials: MK
authors.lastname: Samur
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Naoya
authors.initials: N
authors.lastname: Mimura
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Rikio
authors.initials: R
authors.lastname: Suzuki
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Yu-Tzu
authors.initials: YT
authors.lastname: Tai
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Ruben D
authors.initials: RD
authors.lastname: Carrasco
authors.affiliation: MGH Cancer Center, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Noopur
authors.initials: N
authors.lastname: Raje
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Paul G
authors.initials: PG
authors.lastname: Richardson
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.|West Roxbury Division, VA Boston Healthcare System, West Roxbury, MA 02132, USA.
authors.forename: Nikhil C
authors.initials: NC
authors.lastname: Munshi
authors.affiliation: Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980-8574, Japan.
authors.forename: Hideo
authors.initials: H
authors.lastname: Harigae
authors.affiliation: Cancer Science Institute of Singapore, Department of Medicine, National University of Singapore, Singapore 117599, Singapore.
authors.forename: Takaomi
authors.identifier: http://orcid.org/0000-0003-1621-4954
authors.initials: T
authors.lastname: Sanda
authors.affiliation: Division of Metabolic Medicine, Research Center for Advanced Science and Technology, University of Tokyo, Tokyo 153-8904, Japan.
authors.forename: Juro
authors.initials: J
authors.lastname: Sakai
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D002448:Cell Adhesion / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D055785:Gene Knockdown Techniques; D006657:Histones / Q000378:metabolism; D006801:Humans; D050835:Interferon Regulatory Factors / Q000235:genetics / Q000378:metabolism*; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism*; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009101:Multiple Myeloma / Q000378:metabolism*; D000099218:Interferon Regulatory Factor-4
chemical_list: D006657:Histones; D050835:Interferon Regulatory Factors; D056484:Jumonji Domain-Containing Histone Demethylases; D051741:Kruppel-Like Transcription Factors; D000099218:Interferon Regulatory Factor-4; C096161:KLF2 protein, human; C530247:KDM3A protein, human