# Targeting Menin Protein Stability In AML

> **NIH NIH K99** · DANA-FARBER CANCER INST · 2024 · $129,600

## Abstract

PROJECT SUMMARY
Multiple Endocrine Neoplasia Type 1 (MEN1/MENIN) is a transcriptional regulator known to interact with
Lysine Methyltransferase 2A (KMT2A/MLL1) driving aggressive subsets of leukemia including MLL1
rearranged (MLL-r), NPM1 mutated and NUP98 rearranged acute myeloid leukemia (AML) as well as other
cancers including gastrointestinal stromal tumors. Early success has been reported in clinical trials using
small molecule MENIN inhibitors (MI) that disrupt the MLL1/MENIN interaction to treat AML causing MENIN
to emerge as an important drug target. As a result, efforts to understand MENIN function are paramount for
the continued success of targeting this protein. I, as a research fellow working under the mentorship of Drs.
Scott Armstrong and Eric Fischer, have recently characterized an exciting aspect of the mechanism driving
the therapeutic effect of MI treatments. We have observed that protein stability changes to MENIN and other
proteins is an essential feature of MI sensitivity. Our preliminary examination of this mechanism has
uncovered that the loss of a specific E3 ligase can mediate decreased MI sensitivities via MENIN protein
stabilization. These findings have inspired a new approach of targeting MENIN protein stability with the
simple idea that more MENIN protein decreases drug sensitivity while less MENIN protein inhibits MLL-r
transcriptional programs. The experiments outline in this proposal aim to characterize MENIN protein
stability in AML by studying how this specific E3 ligase regulates MENIN contributing to MI sensitivity and
investigate newly established rapid MENIN degradation systems as a proof-of-principle for improving both
MENIN targeted therapies as well as the means to study MENIN function. We have recently established a
novel set of tools to study MENIN protein function including (i) MLL-r leukemia cell lines with edited MEN1
loci inserting different protein tags enabling high throughput MENIN protein stability reporter systems and
dTAG based rapid MENIN degradation systems, (ii) specific CRISPR libraries targeting MENIN protein
function and (iii) early candidate small molecule MENIN proteolysis targeting chimeras (PROTAC). This
proposal is also designed to provide additional training experiences in advanced methods of transcriptional
analysis, biochemical binding assays, small molecule PROTAC design and mass spectrometry-based co-
immunoprecipitation as well as mentoring in manuscript/grant writing and leadership skills. Anchored by the
guidance of two well-resourced and established mentors, an excellent scientific advisory committee
composed of experts in the fields of leukemia and chromatin biology and a highly dynamic research
environment at DCFI, funding for this proposal will enable me to transition to an independent investigator.

## Key facts

- **NIH application ID:** 10890035
- **Project number:** 5K99CA279888-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Jevon Cutler
- **Activity code:** K99 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $129,600
- **Award type:** 5
- **Project period:** 2023-07-18 → 2025-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10890035

## Citation

> US National Institutes of Health, RePORTER application 10890035, Targeting Menin Protein Stability In AML (5K99CA279888-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10890035. Licensed CC0.

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