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

Cancer Cell. 2019 May 13;35(5):752-766.e9. doi: 10.1016/j.ccell.2019.04.005.


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.

Keywords: ABT-199; BCL2; CDK7; THZ1; double-hit lymphoma; drug persister; drug resistance; mantle cell lymphoma; super-enhancer remodeling; transcriptome reprogramming.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural