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Loss of COP9 signalosome genes at 2q37 is associated with IMiD resistance in multiple myeloma

Gooding, Sarah; Ansari-Pour, Naser; Kazeroun, Mohammad H; Karagoz, Kubra; Polonskaia, Ann; Angulo Salazar, Mirian; Fitzsimons, Evelyn; ... Thakurta, Anjan; + view all (2022) Loss of COP9 signalosome genes at 2q37 is associated with IMiD resistance in multiple myeloma. Blood , 140 (16) pp. 1816-1821. 10.1182/blood.2022015909. Green open access

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Abstract

The acquisition of a multi-drug refractory state is a major cause of mortality in myeloma. Myeloma drugs that target the Cereblon (CRBN) protein include widely-used immunomodulatory drugs (IMiDs), and newer CRBN E3 ligase modulator drugs (CELMoDs), in clinical trials. CRBN genetic disruption causes resistance and poor outcomes with IMiDs. Here we investigate alternative genomic associations of IMiD resistance, using large whole genome sequencing patient datasets (n=522 cases) at newly diagnosed, lenalidomide (LEN)-refractory and lenalidomide-then-pomalidomide (LEN-then-POM)-refractory timepoints. Selecting gene targets reproducibly identified by published CRISPR/shRNA IMiD resistance screens, we found little evidence of genetic disruption by mutation associated with IMiD resistance. However, we identified a chromosome region, 2q37, containing COP9-signalosome members COPS7b and COPS8, copy loss of which significantly enriches between newly-diagnosed (incidence 5.5%), LEN-refractory (10.0%) and LEN-then-POM-refractory states (16.4%), and may adversely affect outcomes when clonal fraction is high. In a separate dataset (50 patients) with sequential samples taken throughout treatment, we identified acquisition of 2q37 loss in 16% cases with IMiD exposure, but none in cases without IMiD exposure. The COP9 signalosome is essential for maintenance of the CUL4-DDB1-CRBN E3 Ubiquitin Ligase. This region may represent a novel marker of IMiD resistance with clinical utility.

Type: Article
Title: Loss of COP9 signalosome genes at 2q37 is associated with IMiD resistance in multiple myeloma
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1182/blood.2022015909
Publisher version: https://doi.org/10.1182/blood.2022015909
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Lymphoid Neoplasia, Multiple Myeloma
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Haematology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
URI: https://discovery.ucl.ac.uk/id/eprint/10153068
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