The KDM3A–KLF2–IRF4 axis maintains myeloma cell survival
Copyright policy )The KDM3A–KLF2–IRF4 axis maintains myeloma cell survival
AbstractKDM3A 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.
- Harvard University United States
- National University of Singapore Singapore
- National University of Singapore Libraries Singapore
- University of Tokyo Japan
- University of Genoa Italy
Jumonji Domain-Containing Histone Demethylases, 590, KLF2 protein, animal cell, nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase, bone, Histones, gene silencing, caspase 7, caspase 8, histone H3, Cell Movement, cell interaction, histone demethylation, autoregulation, Q, apoptosis, unclassified drug, multiple myeloma, Gene Expression Regulation, Neoplastic, interferon regulatory factor, Gene Knockdown Techniques, Interferon Regulatory Factors, Multiple Myeloma, immunoblotting, protein KDM3A, tumor, anatomy, bone marrow, in vitro study, Science, interferon regulatory factor 4, animal experiment, Kruppel-Like Transcription Factors, 610, histone, cell survival, Article, animal tissue, in vivo study, interferon regulatory factor-4, male, histone demethylase, Cell Line, Tumor, Cell Adhesion, bone marrow stroma cell, Humans, controlled study, human, mouse, animal model, human cell, kruppel like factor, cell adhesion, KDM3A protein, kruppel like factor 2, monoclonal immunoglobulinemia, gene expression, Interferon Regulatory Factor-4, microarray analysis, cells and cell components, cell homing
Jumonji Domain-Containing Histone Demethylases, 590, KLF2 protein, animal cell, nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase, bone, Histones, gene silencing, caspase 7, caspase 8, histone H3, Cell Movement, cell interaction, histone demethylation, autoregulation, Q, apoptosis, unclassified drug, multiple myeloma, Gene Expression Regulation, Neoplastic, interferon regulatory factor, Gene Knockdown Techniques, Interferon Regulatory Factors, Multiple Myeloma, immunoblotting, protein KDM3A, tumor, anatomy, bone marrow, in vitro study, Science, interferon regulatory factor 4, animal experiment, Kruppel-Like Transcription Factors, 610, histone, cell survival, Article, animal tissue, in vivo study, interferon regulatory factor-4, male, histone demethylase, Cell Line, Tumor, Cell Adhesion, bone marrow stroma cell, Humans, controlled study, human, mouse, animal model, human cell, kruppel like factor, cell adhesion, KDM3A protein, kruppel like factor 2, monoclonal immunoglobulinemia, gene expression, Interferon Regulatory Factor-4, microarray analysis, cells and cell components, cell homing
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