# Understanding the unique dependency for MCL1 in Ven/Aza resistant AML

> **NIH NIH F32** · UNIVERSITY OF COLORADO DENVER · 2022 · $69,220

## Abstract

PROJECT SUMMARY/ ABSTRACT
Despite extensive efforts aimed toward the development of improved molecular therapies targeting acute
myeloid leukemia (AML), clinical outcomes remain poor. Of particular interest, is the necessary and selective
therapeutic targeting of disease initiating leukemia stem cells (LSC). The Jordan laboratory has reported that
LSC are functionally reliant upon BCL2 for cellular oxidative phosphorylation (OXPHOS) requirements. Targeting
BCL2 with venetoclax (Ven) in combination with azacitidine (Aza) has clinically delivered significant responses
in newly diagnosed AML patients, however both upfront refractory and relapsed diseases are still a major
obstacle. Notably, we show that Ven/Aza resistant AML express elevated MCL1 protein and OXPHOS levels.
Moreover, the Jordan laboratory have recently reported that pharmacologic perturbation of MCL1 in resistant
specimens leads to a selective decrease in OXPHOS output as well as reduced LSC functional ability as
measured by engraftment of immune deficient mice. Continued analysis of Ven/Aza resistant AML highlighted a
significant increase in mitochondrial fission promoting DRP1 phosphorylation as well as in metabolomic
enrichment of fatty acid oxidation. Thus, we hypothesize that MCL1 specifically drives Ven/Aza resistance by
promoting mitochondrial fission and β-oxidation. As this proposal aims to define the mechanisms through which
MCL1 uniquely influences therapy resistance in AML, our studies will largely utilize Ven/Aza resistant primary
AML specimens to interrogate the specific role of MCL1 in regulating mitochondrial function through fission and
β-oxidation. Successful completion of these studies will generate a detailed and mechanistic understanding of
the non-canonical roles for MCL1 in regulating mitochondrial morphology and lipid metabolism, while also
providing alternative approaches for therapeutic intervention in therapy resistant AML.

## Key facts

- **NIH application ID:** 10535785
- **Project number:** 1F32CA275350-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Mark Jordan Althoff
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $69,220
- **Award type:** 1
- **Project period:** 2022-07-13 → 2025-07-12

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10535785

## Citation

> US National Institutes of Health, RePORTER application 10535785, Understanding the unique dependency for MCL1 in Ven/Aza resistant AML (1F32CA275350-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10535785. Licensed CC0.

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