# Targeting non-genetic and genetic mechanisms to overcome drug resistance in acute myeloid leukemia

> **NIH CA R01** · EMORY UNIVERSITY · 2026 · $639,859

## Abstract

PROJECT SUMMARY
Most patients diagnosed with acute myeloid leukemia (AML) die of the disease due to development of
resistance to existing chemotherapy or targeted therapy. This problem underscores the compelling
need for understanding of relapse emergence mechanisms and identification of effective targeted
strategies to overcome leukemia relapse.
Recently, by using dynamic BH3 profiling that measures rapid change in drug-induced apoptotic
signaling, we identified drugs that can overcome resistance to venetoclax, a selective BCL-2 inhibitor
and active drug in leukemia (Bhatt et al, Cancer Cell 2020). Through mechanistic studies using patient
derived xenograft (PDX) models, we next found venetoclax resistance emergence is accompanied by
reduced sensitivity of mitochondria to apoptotic signaling mechanisms. Surprisingly, we found that
resistance to disparate, narrowly-targeted agents in distinct PDX models was consistently
accompanied by broad resistance to a wide variety of drugs, indicative of multi-resistance phenotype
at relapse (Olesinski et al, Blood Cancer Discovery, 2024). We then reported that selection for reduced
mitochondrial priming drives multi-drug resistance phenotype at relapse. By building upon these
findings, we hypothesize that stable acquired resistance emerges from drug-tolerant leukemic persister
cells and that the persister cells can be targeted by exploiting mitochondrial apoptotic signaling
mechanisms.
To address this, we propose to utilize Watermelon 2.0 library an innovative lentiviral construct that
contains both an expressed barcode, and an inducible histone-2B (H2B-mCherry) florescent dilution
system, to trace in vivo clonal evolution. In Aim 1, we will look for an evidence of both genetic and non-
genetic modes of clonal evolution of resistance using high-complexity DNA barcoding, proliferative
index, and whole genome studies. In Aim 2, we will identify cellular states that contribute to persister
development by single-cell transcriptomi

## Key facts

- **NIH application ID:** 11298655
- **Project number:** 1R01CA297078-01A1
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Shruti  Bhatt
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** CA
- **Fiscal year:** 2026
- **Award amount:** $639,859
- **Award type:** 1
- **Project period:** 2026-05-01T00:00:00 → 2031-04-30T00:00:00

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11298655

## Citation

> US National Institutes of Health, RePORTER application 11298655, Targeting non-genetic and genetic mechanisms to overcome drug resistance in acute myeloid leukemia (1R01CA297078-01A1). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/11298655. Licensed CC0.

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