# Epigenetic Regulation of Drug Resistance to ABT-199 in B-cell Malignancies

> **NIH NIH R21** · H. LEE MOFFITT CANCER CTR & RES INST · 2020 · $187,050

## Abstract

While enormous effort has gone into understanding the molecular events in acquired resistance, not much
attention has been given to what happens during treatment, particularly during the early phase when patients
still respond to drug treatment. Venetoclax (ABT-199), a novel potent and selective small-molecule BCL-2
inhibitor, has recently emerged as an effective therapy for hematopoietic tumors including MCL. While
responses to ABT-199 can often be dramatic, they are rarely durable, and there is a significant need to
improve the duration of response and delay or prevent drug resistance (DR). We modeled drug resistance to
ABT-199 by generating ABT-199 resistant cell lines from MCL, and characterized the adaptive molecular
reprogramming to ABT-199 treatment in MCL lines and primary samples. More complex and more dynamic
than we had anticipated, we consistently detected a small subpopulations of lymphoma cells that evade strong
selective ABT-199 pressure by entering a reversible drug tolerant 'persister' state (DTP), leading to DTP
expansion population (DTEP) and eventual acquisition of bona fide drug resistance. We observed that these
DTEP cells are conferred increased survival, clonogenic growth and are associated with BH3 family protein
reprogramming. Intriguingly, DTEP cells revert back to drug sensitive states after long term passage without
the drug, supporting that these cells are epigenetically reprogrammed to drug resistant states. Consistent with
these results, by using drug screen approaches, we observed that epigenetic regulators such as BRD4,
PRMT5, CDK9 and EP300 are required for and contribute to drug tolerance and drug resistance evolution.
Most recently, RNA sequencing (RNA-seq) and ChIP-seq against H3K27Acrevealed super-enhancers (SE)
remodeling in DTEP cells, supporting that epigenetically regulated SEs remodeling is required for
transcriptional reprogramming and drug resistance evolution. Our central hypothesis is that transcriptional and
epigenetic adaptive response and coordination in response to ABT-199 treatment confer MCL drug tolerance
and therapeutic vulnerability to prevent subsequent drug resistance evolution in MCL. The objective of this
proposal is to strategically target epigenetic transcription machinery and provide pre-clinical validation of
combination of epigenetically targeting with BCL-2 antagonist as a therapeutic approach against MCL. The
study allows us to gain valuable insights into MCL drug resistance biology and uncover a novel mechanism-
driven therapy for MCL patients.

## Key facts

- **NIH application ID:** 9904591
- **Project number:** 5R21CA234519-02
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** John L. Cleveland
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $187,050
- **Award type:** 5
- **Project period:** 2019-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9904591

## Citation

> US National Institutes of Health, RePORTER application 9904591, Epigenetic Regulation of Drug Resistance to ABT-199 in B-cell Malignancies (5R21CA234519-02). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9904591. Licensed CC0.

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