Loss Of COP9-signalosome genes Aa 2q37 is associated with IMiD agent resistance in multiple myeloma
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...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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American Society of Hematology
2022
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| _version_ | 1826308987999485952 |
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| author | Gooding, S Ansari-Pour, N Kazeroun, MH Karagoz, K Polonskaia, A Angulo Salazar, M Fitzsimons, E Sirinukunwattana, K Chavda, SJ Ortiz Estevez, M Towfic, F Flynt, E Pierceall, W Royston, D Yong, KL Ramasamy, K Vyas, P Thakurta, A |
| author_facet | Gooding, S Ansari-Pour, N Kazeroun, MH Karagoz, K Polonskaia, A Angulo Salazar, M Fitzsimons, E Sirinukunwattana, K Chavda, SJ Ortiz Estevez, M Towfic, F Flynt, E Pierceall, W Royston, D Yong, KL Ramasamy, K Vyas, P Thakurta, A |
| author_sort | Gooding, S |
| collection | OXFORD |
| description | 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. |
| first_indexed | 2024-03-07T07:27:32Z |
| format | Journal article |
| id | oxford-uuid:861f7772-ece3-40c6-b2f7-9b87798f276c |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T07:27:32Z |
| publishDate | 2022 |
| publisher | American Society of Hematology |
| record_format | dspace |
| spelling | oxford-uuid:861f7772-ece3-40c6-b2f7-9b87798f276c2022-11-25T14:23:03ZLoss Of COP9-signalosome genes Aa 2q37 is associated with IMiD agent resistance in multiple myelomaJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:861f7772-ece3-40c6-b2f7-9b87798f276cEnglishSymplectic ElementsAmerican Society of Hematology2022Gooding, SAnsari-Pour, NKazeroun, MHKaragoz, KPolonskaia, AAngulo Salazar, MFitzsimons, ESirinukunwattana, KChavda, SJOrtiz Estevez, MTowfic, FFlynt, EPierceall, WRoyston, DYong, KLRamasamy, KVyas, PThakurta, AThe 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. |
| spellingShingle | Gooding, S Ansari-Pour, N Kazeroun, MH Karagoz, K Polonskaia, A Angulo Salazar, M Fitzsimons, E Sirinukunwattana, K Chavda, SJ Ortiz Estevez, M Towfic, F Flynt, E Pierceall, W Royston, D Yong, KL Ramasamy, K Vyas, P Thakurta, A Loss Of COP9-signalosome genes Aa 2q37 is associated with IMiD agent resistance in multiple myeloma |
| title | Loss Of COP9-signalosome genes Aa 2q37 is associated with IMiD agent resistance in multiple myeloma |
| title_full | Loss Of COP9-signalosome genes Aa 2q37 is associated with IMiD agent resistance in multiple myeloma |
| title_fullStr | Loss Of COP9-signalosome genes Aa 2q37 is associated with IMiD agent resistance in multiple myeloma |
| title_full_unstemmed | Loss Of COP9-signalosome genes Aa 2q37 is associated with IMiD agent resistance in multiple myeloma |
| title_short | Loss Of COP9-signalosome genes Aa 2q37 is associated with IMiD agent resistance in multiple myeloma |
| title_sort | loss of cop9 signalosome genes aa 2q37 is associated with imid agent resistance in multiple myeloma |
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