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The MLL-Menin Interaction is a Therapeutic Vulnerability in NUP98-rearranged AML

Lookup NU author(s): Dr Helen Blair, Dr Katarzyna SzoltysekORCiD, Rachel Cameron, Professor Olaf Heidenreich

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2023 Wolters Kluwer Health. All rights reserved. Chromosomal translocations involving the NUP98 locus are among the most prevalent rearrangements in pediatric acute myeloid leukemia (AML). AML with NUP98 fusions is characterized by high expression of HOXA and MEIS1 genes and is associated with poor clinical outcome. NUP98 fusion proteins are recruited to their target genes by the mixed lineage leukemia (MLL) complex, which involves a direct interaction between MLL and Menin. Here, we show that therapeutic targeting of the Menin-MLL interaction inhibits the propagation of NUP98-rearrranged AML both ex vivo and in vivo. Treatment of primary AML cells with the Menin inhibitor revumenib (SNDX-5613) impairs proliferation and clonogenicity ex vivo in long-term coculture and drives myeloid differentiation. These phenotypic effects are associated with global gene expression changes in primary AML samples that involve the downregulation of many critical NUP98 fusion protein-target genes, such as MEIS1 and CDK6. In addition, Menin inhibition reduces the expression of both wild-type FLT3 and mutated FLT3-ITD, and in combination with FLT3 inhibitor, suppresses patient-derived NUP98-r AML cells in a synergistic manner. Revumenib treatment blocks leukemic engraftment and prevents leukemia-associated death of immunodeficient mice transplanted with NUP98::NSD1 FLT3-ITD-positive patient-derived AML cells. These results demonstrate that NUP98-rearranged AMLs are highly susceptible to inhibition of the MLL-Menin interaction and suggest the inclusion of AML patients harboring NUP98 fusions into the clinical evaluation of Menin inhibitors.

Publication metadata

Author(s): Rasouli M, Blair H, Troester S, Szoltysek K, Cameron R, Ashtiani M, Krippner-Heidenreich A, Grebien F, McGeehan G, Zwaan CM, Heidenreich O

Publication type: Article

Publication status: Published

Journal: HemaSphere

Year: 2023

Volume: 7

Issue: 8

Print publication date: 01/08/2023

Acceptance date: 21/06/2023

Date deposited: 09/01/2024

ISSN (electronic): 2572-9241

Publisher: Wolters Kluwer Health

URL: https://doi.org/10.1097/HS9.0000000000000935

DOI: 10.1097/HS9.0000000000000935

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