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 C.S. Huang, George Grigoriadis, Julie Tellier, Stephen L. Nutt

Research output: Contribution to journalArticleResearchpeer-review

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 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.

Original languageEnglish
Pages (from-to)2166-2178
Number of pages13
JournalBlood
Volume132
Issue number20
DOIs
Publication statusPublished - 15 Nov 2018

Cite this

Fedele, Pasquale L. ; Willis, Simon N. ; Liao, Yang ; Low, Michael S. ; Rautela, Jai ; Segal, David H. ; Gong, Jia Nan ; Huntington, Nicholas D. ; Shi, Wei ; Huang, David C.S. ; Grigoriadis, George ; Tellier, Julie ; Nutt, Stephen L. / IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos. In: Blood. 2018 ; Vol. 132, No. 20. pp. 2166-2178.
@article{c48d47171bd04595b955477159321496,
title = "IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos",
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 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.",
author = "Fedele, {Pasquale L.} and Willis, {Simon N.} and Yang Liao and Low, {Michael S.} and Jai Rautela and Segal, {David H.} and Gong, {Jia Nan} and Huntington, {Nicholas D.} and Wei Shi and Huang, {David C.S.} and George Grigoriadis and Julie Tellier and Nutt, {Stephen L.}",
year = "2018",
month = "11",
day = "15",
doi = "10.1182/blood-2018-05-850727",
language = "English",
volume = "132",
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Fedele, PL, Willis, SN, Liao, Y, Low, MS, Rautela, J, Segal, DH, Gong, JN, Huntington, ND, Shi, W, Huang, DCS, Grigoriadis, G, Tellier, J & Nutt, SL 2018, 'IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos' Blood, vol. 132, no. 20, pp. 2166-2178. https://doi.org/10.1182/blood-2018-05-850727

IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos. / Fedele, Pasquale L.; Willis, Simon N.; Liao, Yang; Low, Michael S.; Rautela, Jai; Segal, David H.; Gong, Jia Nan; Huntington, Nicholas D.; Shi, Wei; Huang, David C.S.; Grigoriadis, George; Tellier, Julie; Nutt, Stephen L.

In: Blood, Vol. 132, No. 20, 15.11.2018, p. 2166-2178.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of Ikaros and Aiolos

AU - Fedele, Pasquale L.

AU - Willis, Simon N.

AU - Liao, Yang

AU - Low, Michael S.

AU - Rautela, Jai

AU - Segal, David H.

AU - Gong, Jia Nan

AU - Huntington, Nicholas D.

AU - Shi, Wei

AU - Huang, David C.S.

AU - Grigoriadis, George

AU - Tellier, Julie

AU - Nutt, Stephen L.

PY - 2018/11/15

Y1 - 2018/11/15

N2 - 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.

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U2 - 10.1182/blood-2018-05-850727

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