Journal article

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

Pasquale L Fedele, Simon N Willis, Yang Liao, Michael S Low, Jai Rautela, David H Segal, Jia-Nan Gong, Nicholas D Huntington, Wei Shi, David CS Huang, George Grigoriadis, Julie Tellier, Stephen L Nutt

BLOOD | AMER SOC HEMATOLOGY | Published : 2018

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 treatm..

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Grants

Awarded by National Health and Medical Research Council (NHMRC) Australia


Awarded by NHMRC Australia


Awarded by Royal Australasian College of Physicians


Awarded by Leukemia and Lymphoma Society Specialized Center of Research Grant


Funding Acknowledgements

This project was supported by research grants from the National Health and Medical Research Council (NHMRC) Australia (1054618 and 1058238 to S.L.N, 1016701 to D.C.S.H.). The study was partly funded by the Cancer Council Victoria's Grant-in-Aid Scheme (to S.L.N.). P.L.F. was supported by a Leukaemia Foundation of Australia Clinical Scholarship and a Royal College of Pathologists of Australasia Foundation Postgraduate Research Fellowship, S.N.W. by The Walter and Eliza Hall Trust Centenary Fellowship, M.S.L. by a CRB Blackburn scholarship (GNT1075151) jointly from the NHMRC Australia and Royal Australasian College of Physicians, W.S. was supported by a Walter and Eliza Hall Centenary Fellowship sponsored by Commonwealth Serum Laboratories Limited, and D.C.S.H. by an NHMRC Australia fellowship and funding from the Leukemia and Lymphoma Society Specialized Center of Research Grant (7001-13). This work was made possible through Victorian State Government Operational Infrastructure Support and NHMRC Independent Research Institute Infrastructure Support Scheme.