IMiDs through loss of Ikaros and Aiolos primes myeloma cells for daratumumab mediated killing by upregulation of CD38
Journal Title
Blood
Publication Type
Journal Article in press
Abstract
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 remodelling 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.
Publisher
ASH
WEHI Research Division(s)
Cancer And Haematology; Molecular Immunology; Bioinformatics
PubMed ID
30228232
Rights Notice
Refer to copyright notice on published article.


Creation Date: 2018-09-21 02:32:23
Last Modified: 2018-09-21 02:39:21
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