Abstract 4306: KMT2A rearranged acute myeloid leukemia is vulnerable to the combinatorial inhibition of menin and MYC protein degradation

Abstract Background: Menin is the scaffolding protein part of the mixed lineage leukemia (MLL) histone methyltransferase complex and uniquely acts as both a tumor suppressor and oncogenic cofactor. KMT2A or MLL rearranged (KMT2Ar) leukemias are a distinct group with poor prognosis and a median overall survival of 0.9 years (Issa, 2021). This interaction has been targeted by menin inhibitors revunemib and ziftomenib with promising results in clinical trials (Aldoss & Issa, 2023; Erba, 2022), and revumenib is now FDA-approved. Menin directly interacts with the TAD domain of c-MYC (MYC) and amplifies MYC’s transcriptional activities (Wu, 2017). We have investigated GT19715, the first-in-class MYC/GSPT1 degrader in MYC-driven hematological malignancies (Nishida, ASH 2022, 2023, 2024). We hypothesized that combined menin inhibition and MYC degradation induces synergistic cytotoxicity in KMT2Ar AML. Methods: MOLM-13 CRISPR-generated isogenic cells with wild-type (WT), knockout (KO), or mutant TP53 (R175H, Y220C, M237I, R248Q, R237H, and R282W), MV411 and OCI-AML2 cell lines were exposed to menin inhibitor SNDX-50469 (SNDX) (selleckchem) in combination with GT19715 (GT). Cell death was determined by annexin V/DAPI assays. Time course experiments were conducted in MOLM13 WT, KO, Y220C and R282W cells. Bliss synergy scores (BSS) > 10 are considered synergistic. MOLM-13 cells WT and Y220C mutation labeled with GFP/luciferase were injected into NSG mice and SNDX and/or GT were administered. Results: The combination treatment (100 or 400 nM SNDX and 2 or 4 nM GT) significantly induced cell death and reduced cell numbers by > 99% (> log10^2 difference), starting at day 2 (WT and KO) or 3 (Y220C and R282W) compared to SNDX or GT monotherapy. SNDX + GT induced synergistic cell death (BSS > 10) in all cell lines tested with BSSs up to 80, suggesting substantial synergistic effects by menin inhibition combined with MYC protein degradation. We injected MOLM-13 TP53 WT GFP/Luc and MOLM-13 TP53 Y220C GFP/Luc cell lines (0.5 e6/mouse through tail veins) into NSG mice. After confirming engraftment determined by bioluminescence imaging (BLI), we treated mice with vehicle, GT (3 times a week, every other day by IP injections), SNDX (PO, QD) or GT + SNDX combination for 6 weeks. The combination treatment reduced the total BLI signals at week 2 by 10^4, 10^4 and 10^2 compared to vehicle, GT or SNDX alone. The data suggest the combinatorial treatment of SNDX with GT synergistically reduced leukemia burden in vivo. Conclusion: Combinatorial approach of menin inhibition and MYC degradation results in a profound synergistic reduction of KMT2Ar AML cells in vitro and in vivo, validating the underlying premise. Further mechanistic studies and efficacy in PDX models are ongoing. Citation Format: Shreya Nair, Shayaun Khazaei, Lauren B. Ostermann, Hideaki Mizuno, Po Yee Mak, Bing Z. Carter, Steffen Boettcher, Liandong Ma, Miriam B. Garcia, Branko Cuglievan, Michael Andreeff, Yuki Nishida. KMT2A rearranged acute myeloid leukemia is vulnerable to the combinatorial inhibition of menin and MYC protein degradation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4306.