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Characterizing and targeting acquired resistance to menin-KMT2A inhibitors in acute myeloid leukemia.

Award Number: K08CA304374
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/01/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2031

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Characterizing and targeting acquired resistance to menin-KMT2A inhibitors in acute myeloid leukemia. - Advances in drug development have enabled targeting of multi-protein, oncogenic chromatin complexes that drive many cancers. Acute myeloid leukemia (AML) has a poor prognosis despite intensive chemotherapy regimens. KMT2A gene rearrangements (KMT2A-r) or nucleophosmin mutations (NPM1c) are found in ~40% of AML cases and exhibit aberrant expression of MEIS1/HOXA cluster genes and dependence on the menin- KMT2A protein-protein interaction (PPI). Menin inhibitors (MIs) are PPI inhibitors that bind to menin, displace menin and KMT2A proteins from chromatin at key loci such as MEIS1, and cause leukemia cell differentiation. 5 MIs have entered clinical trials and the MI SNDX-5613 earned food and drug administration (FDA) approval in 2024 for relapsed or refractory KMT2A-r AML. However, acquired menin/MEN1 mutations arose in ~40% of patients after only 2 cycles of SNDX-5613 and attenuate MI activity by disrupting MI binding to menin protein. I hypothesize that I have uncovered a novel form of resistance to MIs with broad implications for PPI inhibitors and chromatin-targeting therapies: acquired, gain-of-function mutations in an oncogenic chromatin complex (composed of menin, KMT2A, and PSIP1) that strengthen protein-protein interactions and resist PPI inhibitor-induced displacement of chromatin complex members from chromatin. In this proposal, I will profile patient samples to identify further mutations in this complex and the sites where they occur (Aim 1a), discern how these mutations resist MI-induced gene expression and chromatin occupancy changes (Aim 1b), and perform biochemical studies to prove these mutations strengthen protein-protein binding affinities (Aim 1c). However, resistance to MIs also develops without MEN1/KMT2A/PSIP1 mutations. An MI-induced, minimal residual disease (MRD) state arises in patients and patient derived xenograft (PDX) models treated with prolonged MI therapy. I hypothesize that leukemia stem cells (LSCs) are enriched and drive this MRD state despite on-target MI activity in the bulk, residual leukemia cells. In this proposal, I will define the gene expression changes, immunophenotype, and chromatin accessibility of MI monotherapy-induced MRD at the single cell level (Aim 2a). We have previously shown that the Ikaros protein degrader mezigdomide and MIs synergize, which led us to develop a Phase 1 clinical trial assessing this therapy in relapsed KMT2A-r and NPM1c AML. In these samples, I will test the hypothesis that MRD cells are eliminated due to enhanced, cotargeting of MEIS1 (by MIs) and HOXA9-driven gene expression (by mezigdomide) (Aim 2b). Finally, I will functionally assess leukemia initiating capacity of LSCs following MI mono- and combination therapy (Aim 2c). Immunodeficient mice are required for this study because they permit engraftment and serial transplantation of human leukemia cells as PDXs, enabling assessment of leukemia-initiating capacity and MI-induced MRD. Overall, this work will provide key insights into two novel forms of acquired resistance to a PPI inhibitor targeting an oncogenic chromatin complex: A. Mutations that strengthen protein-protein interactions, thus resisting PPI inhibitor-induced chromatin complex disruption, and B., LSC-driven resistance in an MRD state wherein leukemia initiating capacity is retained despite on-target PPI inhibitor activity in bulk residual cells.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $233,478 )
2026	2026	DANA-FARBER CANCER INSTITUTE, INC.	450 BROOKLINE AVE	BOSTON	MA	02215	SUFFOLK	USA	Cancer Research Manpower	000	1	8/28/2026	NEW	$233,478
														Subtotal = $233,478

Grand Total All Awards = $233,478

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Characterizing and targeting acquired resistance to menin-KMT2A inhibitors in acute myeloid leukemia.

Award Number: K08CA304374

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/01/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2031

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