The KDM3A-KLF2-IRF4 axis maintains myeloma cell survival.
Hiroto OhguchiTeru HideshimaManoj K BhasinGullu T GorgunLoredana SantoMichele CeaMehmet K SamurNaoya MimuraRikio SuzukiYu-Tzu TaiRuben D CarrascoNoopur RajePaul G RichardsonNikhil C MunshiHideo HarigaeTakaomi SandaJuro SakaiKenneth C AndersonPublished in: Nature communications (2016)
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.
Keyphrases
- bone marrow
- cell cycle arrest
- dendritic cells
- induced apoptosis
- transcription factor
- mesenchymal stem cells
- multiple myeloma
- poor prognosis
- cell death
- endoplasmic reticulum stress
- oxidative stress
- stem cells
- cell therapy
- single cell
- immune response
- cell proliferation
- signaling pathway
- binding protein
- long non coding rna
- newly diagnosed