IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos.

Autor:	Fedele PL; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.; Haematology Department, Monash Health, Clayton, VIC, Australia., Willis SN; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia., Liao Y; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia., Low MS; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.; Haematology Department, Monash Health, Clayton, VIC, Australia., Rautela J; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia., Segal DH; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia., Gong JN; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia., Huntington ND; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia., Shi W; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Computing and Information Systems, The University of Melbourne, Parkville, VIC, Australia; and., Huang DCS; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia., Grigoriadis G; Haematology Department, Monash Health, Clayton, VIC, Australia.; School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC, Australia., Tellier J; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia., Nutt SL; The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia.; Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2018 Nov 15; Vol. 132 (20), pp. 2166-2178. Date of Electronic Publication: 2018 Sep 18.
DOI:	10.1182/blood-2018-05-850727
Abstrakt:	Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1 /Ikaros and IKZF3 /Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis. Furthermore, evaluation of the transcriptional changes resulting from their loss demonstrates striking overlap with lenalidomide treatment. This was not dependent on reduction of the IRF4-MYC "axis," as neither protein was consistently downregulated, despite cell death occurring, and overexpression of either factor failed to rescue for Ikaros loss. Importantly, Ikaros and Aiolos repress the expression of interferon-stimulated genes (ISGs), including CD38 , and their loss led to the activation of an interferon-like response, contributing to MM cell death. Ikaros/Aiolos repressed CD38 expression through interaction with the nucleosome remodeling and deacetylase complex in MM. IMiD-induced loss of Ikaros or treatment with interferon resulted in an upregulation of CD38 surface expression on MM cells, priming for daratumumab-induced NK cell-mediated antibody-dependent cellular cytotoxicity. These results give further insight into the mechanism of action of the IMiDs and provide mechanistic rationale for combination with anti-CD38 monoclonal antibodies. (© 2018 by The American Society of Hematology.)
Databáze:	MEDLINE
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