The transcription factor IKAROS is essential to maintaining a leukemogenic gene-expression profile mediated by transcription factors encoded by HOXA@ and MEIS1 in MLL1-rearranged (MLL-r) acute myeloid leukemia. Pharmacological degradation of IKAROS increases the effectiveness of inhibitors of the MLL1–MENIN protein–protein interaction, which leads to more-robust disruption of leukemogenic transcriptional networks and enhanced therapeutic benefit in preclinical models.
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References
Yokoyama, A. et al. The menin tumor suppressor protein is an essential oncogenic cofactor for MLL-associated leukemogenesis. Cell 123, 207–218 (2005). This paper reports the discovery of menin as an essential protein and therapeutic target in MLL-r AML.
Krivtsov, A. V. et al. A menin-MLL inhibitor induces specific chromatin changes and eradicates disease in models of MLL-rearranged leukemia. Cancer Cell 36, 660–673.e11 (2019). This paper provides pre-clinical rationale for the entry of VTP-50469-based MENIN inhibitors into clinical trials of MLL-r leukemia.
Klossowski, S. et al. Menin inhibitor MI-3454 induces remission in MLL1-rearranged and NPM1-mutated models of leukemia. J. Clin. Invest. 130, 981–997 (2020). This paper provides pre-clinical rationale for the entry of MI-3454-based MENIN inhibitors into clinical trials of AML associated with MLL-r and NPM1 mutations.
Stein, E. M. et al. Safety and efficacy of Menin inhibition in patients (Pts) with MLL-rearranged and NPM1 mutant acute leukemia: a phase (Ph) 1, first-in-human study of SNDX-5613 (AUGMENT 101). Blood 138, 699 (2021). This abstract from the American Society of Hematology Conference in 2021 demonstrates the preliminary efficacy of MENIN inhibitors in a phase 1 trial.
Kühn, M. W. M. et al. Targeting chromatin regulators inhibits leukemogenic gene expression in NPM1 mutant leukemia. Cancer Disc. 6, 1166–1181 (2016). This paper shows that AML associated with NPM1 mutations is dependent on the MENIN–MLL1 interaction and is susceptible to pharmacological inhibition of MENIN–MLL1.
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This is a summary of: Aubrey, B.J. et al. IKAROS and MENIN coordinate therapeutically actionable leukemogenic gene expression in MLL-r acute myeloid leukemia. Nat. Cancer https://doi.org/10.1038/s43018-022-00366-1 (2022).
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Dual targeting of IKAROS and MENIN in MLL-r AML. Nat Cancer 3, 532–533 (2022). https://doi.org/10.1038/s43018-022-00371-4
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DOI: https://doi.org/10.1038/s43018-022-00371-4
