# Effects of microenvironmental modulation on BH3 dependence in AML

> **NIH NIH R03** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $173,000

## Abstract

Abstract
Acute Myeloid Leukemia (AML) is characterized by differentiation blockade and the clonal proliferation of myeloid precursor
cells that culminates in the failure of normal hematopoiesis. Regardless of intensive research efforts, few therapeutic
advancements have been made in past 40 years, and mortality remains high with the overwhelming majority of patients
succumbing to disease within five years of treatment. Overexpression of anti-apoptotic protein, BCL-2, is one hallmark of
AML. A new class of small molecule inhibitors, referred to as BH3 mimetics, selectively target specific BCL-2 family
proteins. Venetoclax (VEN), a selective BCL-2 inhibitor, was recently approved by the FDA in combination with DNA
methyltransferase inhibitors for use in elderly AML patients unfit to receive standard chemotherapy, exhibiting response
rates up to 70%. Despite these remarkable results, primary and acquired VEN resistance remains a concern. We and
others have shown that VEN resistance occurs mainly through the upregulation of another BCL-2 family member, induced
myeloid leukemia cell differentiation protein (MCL-1), and that inhibition of MCL-1 leads to apoptosis in VEN resistant cells.
However, upon further analyses of these underpinnings, we observed discordance in response to BH3 mimetics in the
different hematopoietic compartments of primagraft AML PDX models. BH3 profiling and AML primagraft PDX bone
marrow expansion studies using bone marrow mononuclear cells accurately predict patient specific BH3 dependency, but
we have seen contradictory results in the peripheral blood. Although peripheral cells are often of the same clonality and
differentiation stage as in the bone marrow, our studies indicate that peripheral AML blasts are more sensitive to MCL-1
inhibition in both cell line and patient derived xenografts, regardless of marrow BH3 dependency. Therefore, we
hypothesize that peripheral blast cells in AML are more sensitive to MCL-1 inhibition than those in the bone marrow and
propose that the use of mobilization agents will increase sensitivity of AML cells to MCL-1 inhibition, potentially reducing
the dose of MCL-1 inhibitors needed to achieve response. We will leverage our laboratory’s invaluable resources and
expertise to test this hypothesis with the following aims: 1. Assess the BH3 dependent characteristics of AML blasts
harvested from the bone marrow and periphery of patients and PDX models and 2. Determine the utility of mobilization as
an accessory therapy to enhance BH3 mimetics. These studies will further elucidate the relationship between BCL-2 family
proteins in blast cells and different hematopoietic microenvironments and whether altering the microenvironment can affect
this relationship. Further, as it is well known that the marrow niche provides proliferative and survival advantages that result
in chemotherapy resistance, plerixafor, a CXCR4 agonist, has successfully been used in combination with other agents in
AML as a mobil...

## Key facts

- **NIH application ID:** 10047037
- **Project number:** 1R03CA252807-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Haley Elizabeth Ramsey
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $173,000
- **Award type:** 1
- **Project period:** 2020-07-09 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10047037

## Citation

> US National Institutes of Health, RePORTER application 10047037, Effects of microenvironmental modulation on BH3 dependence in AML (1R03CA252807-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10047037. Licensed CC0.

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