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Myeloma

CSNK1α1 mediates malignant plasma cell survival

Leukemia volume 29, pages 474–482 (2015)Cite this article

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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.

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Acknowledgements

We thank Mei Zheng for performing the histological sections; Reddy Gali, who is part of Harvard Catalyst grant member, for his conduction in microarray analysis; the Microarray and the Flow Cytometry Core Facilities at Dana-Farber Cancer Institute for technical support. This study was supported in part by National Institutes of Health Grants P50-100707, P01-78378 and RO1-50947. KCA is an American Cancer Society Clinical Research Professor.

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Authors and Affiliations

  1. Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma Research, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA

    Y Hu, W Song, D Cirstea, D Lu, N C Munshi & K C Anderson

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Correspondence to K C Anderson.

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Hu, Y., Song, W., Cirstea, D. et al. CSNK1α1 mediates malignant plasma cell survival. Leukemia 29, 474–482 (2015). https://doi.org/10.1038/leu.2014.202

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