CSNK1α1 mediates malignant plasma cell survival

Here we report that targeting casein kinase 1-alpha 1 (CSNK1 alpha 1) is a potential novel treatment strategy in multiple myeloma (MM) therapy distinct from proteasome inhibition. CSNK1 alpha 1 is expressed in all the tested MM cell lines and patient MM cells, and is not altered during bortezomib-triggered cytotoxicity. Inhibition of CSNK1 alpha 1 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. CSNK1 alpha 1 signaling pathways include CDKN1B, P53 and FADD; gene signatures involved included interferon-alpha, tumor necrosis factor-alpha and LIN9. In addition, reduction of Csnk1 alpha 1 prevents cMYC/KRAS12V transformation of BaF3 cells independent of interleukin-3. Impartially, reducing Csnk1 alpha 1 prevented development of cMYC/KRAS12V-induced plasmacytomas in mice, suggesting that CSNK1 alpha 1 may be involved in MM initiation and progression. Our data suggest that targeting CSNK1 alpha 1, alone or combined with bortezomib, is a potential novel therapeutic strategy in MM. Moreover, inhibition of CSNK1 alpha 1 may prevent the progression of monoclonal gammopathy of undetermined significance to MM.