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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.

The KDM3A–KLF2–IRF4 axis maintains myeloma cell survival