title: CSNK1α1 mediates malignant plasma cell survival.
abstract: Here we report that targeting casein kinase 1-α1 (CSNK1α1) is a potential novel treatment strategy in multiple myeloma (MM) therapy distinct from proteasome inhibition. CSNK1α1 is expressed in all the tested MM cell lines and patient MM cells, and is not altered during bortezomib-triggered cytotoxicity. Inhibition of CSNK1α1 kinase activity in MM cells with targeted therapy D4476 or small hairpin RNAs triggers cell G0/G1-phase arrest, prolonged G2/M phase and apoptosis. D4476 also induced cytotoxicity in bortezomib-resistant MM cells and enhanced bortezomib-triggered cytotoxicity. CSNK1α1 signaling pathways include CDKN1B, P53 and FADD; gene signatures involved included interferon-α, tumor necrosis factor-α and LIN9. In addition, reduction of Csnk1α1 prevents cMYC/KRAS12V transformation of BaF3 cells independent of interleukin-3. Impartially, reducing Csnk1α1 prevented development of cMYC/KRAS12V-induced plasmacytomas in mice, suggesting that CSNK1α1 may be involved in MM initiation and progression. Our data suggest that targeting CSNK1α1, alone or combined with bortezomib, is a potential novel therapeutic strategy in MM. Moreover, inhibition of CSNK1α1 may prevent the progression of monoclonal gammopathy of undetermined significance to MM.
authors: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: Y
authors: Y
authors: Hu
authors: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: W
authors: W
authors: Song
authors: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: D
authors: D
authors: Cirstea
authors: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: D
authors: D
authors: Lu
authors: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: N C
authors: NC
authors: Munshi
authors: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors: K C
authors: KC
authors: Anderson
mesh_terms: D000818:Animals; D017209:Apoptosis; D001897:Boronic Acids / Q000737:chemistry; D000069286:Bortezomib; D048128:Casein Kinase Ialpha / Q000502:physiology*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002470:Cell Survival; D018450:Disease Progression; D020869:Gene Expression Profiling; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D008998:Monoclonal Gammopathy of Undetermined Significance / Q000517:prevention & control; D009101:Multiple Myeloma / Q000378:metabolism* / Q000628:therapy; D010950:Plasma Cells / Q000166:cytology*; D010954:Plasmacytoma / Q000628:therapy; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011719:Pyrazines / Q000737:chemistry; D015398:Signal Transduction
chemical_list: D001897:Boronic Acids; D007377:Interleukin-3; D011719:Pyrazines; D000069286:Bortezomib; D048128:Casein Kinase Ialpha; D046988:Proteasome Endopeptidase Complex