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Publication

BCL2 Amplicon Loss and Transcriptional Remodeling Drives ABT-199 Resistance in B Cell Lymphoma Models.

Cancer cell | 2019

Drug-tolerant "persister" tumor cells underlie emergence of drug-resistant clones and contribute to relapse and disease progression. Here we report that resistance to the BCL-2 targeting drug ABT-199 in models of mantle cell lymphoma and double-hit lymphoma evolves from outgrowth of persister clones displaying loss of 18q21 amplicons that harbor BCL2. Further, persister status is generated via adaptive super-enhancer remodeling that reprograms transcription and offers opportunities for overcoming ABT-199 resistance. Notably, pharmacoproteomic and pharmacogenomic screens revealed that persisters are vulnerable to inhibition of the transcriptional machinery and especially to inhibition of cyclin-dependent kinase 7 (CDK7), which is essential for the transcriptional reprogramming that drives and sustains ABT-199 resistance. Thus, transcription-targeting agents offer new approaches to disable drug resistance in B-cell lymphomas.

Pubmed ID: 31085176 RIS Download

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Associated grants

Agency: NCI NIH HHS, United States
Id: R01 CA211336
Agency: NCI NIH HHS, United States
Id: P01 CA066996
Agency: NCI NIH HHS, United States
Id: P30 CA076292
Agency: NCI NIH HHS, United States
Id: R01 CA179062
Agency: NCI NIH HHS, United States
Id: P50 CA100707
Agency: NCI NIH HHS, United States
Id: R01 CA134807
Agency: NCI NIH HHS, United States
Id: R21 CA234519
Agency: NCI NIH HHS, United States
Id: R01 CA137123

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RRID:SCR_014485

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