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Therapeutic implications of menin inhibition in acute leukemias

Abstract

Menin inhibitors are novel targeted agents currently in clinical development for the treatment of genetically defined subsets of acute leukemia. Menin has a tumor suppressor function in endocrine glands. Germline mutations in the gene encoding menin cause the multiple endocrine neoplasia type 1 (MEN1) syndrome, a hereditary condition associated with tumors of the endocrine glands. However, menin is also critical for leukemogenesis in subsets driven by rearrangement of the Lysine Methyltransferase 2A (KMT2A) gene, previously known as mixed-lineage leukemia (MLL), which encodes an epigenetic modifier. These seemingly opposing functions of menin can be explained by its various roles in gene regulation. Therefore, leukemias with rearrangement of KMT2A are predicted to respond to menin inhibition with early clinical data validating this proof-of-concept. These leukemias affect infants, children and adults, and lead to adverse outcomes with current standard therapies. Recent studies have identified novel targets in acute leukemia that are susceptible to menin inhibition, such as mutated Nucleophosmin 1 (NPM1), the most common genetic alteration in adult acute myeloid leukemia (AML). In addition to these alterations, other leukemia subsets with similar transcriptional dependency could be targeted through menin inhibition. This led to rationally designed clinical studies, investigating small-molecule oral menin inhibitors in relapsed acute leukemias with promising early results. Herein, we discuss the physiologic and malignant biology of menin, the mechanisms of leukemia in these susceptible subsets, and future therapeutic strategies using these inhibitors in acute leukemia.

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Fig. 1: Timeline of discoveries leading to investigation of menin inhibitors in acute leukemias.
Fig. 2: Menin structure and function.
Fig. 3: Overview of menin inhibitor targets in leukemia.
Fig. 4: Mechanisms of targeting leukemia through menin inhibition.

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Funding

G.C.I. received funding through the K12 Paul Calabresi Clinical Scholarship Award (NIH/NCI K12 CA088084).

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G.C.I. designed and wrote the manuscript. F.R., C.D.D., E.J., H.M.K., and M.A. provided suggestions and revisions. All authors read and approved the final manuscript.

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Correspondence to Ghayas C. Issa or Michael Andreeff.

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G.C.I. received research funding from Celgene, Kura Oncology, Syndax and Novartis, and received consultancy fees from Novartis and Kura Oncology. F.R. received research funding from Amgen, Bristol-Myers Squibb, Sunesis Pharmaceuticals, Pfizer, Xenecor, Macrogenetics, Taiho, Astex, Abbvie and honoraria for consulting or advisory role from Jazz, Amgen, Celgene, Astellas, Syros, Taiho, Novartis, AstraZeneca, Agios, Bristol Myers Squibb. C.D.D. received research funding from Abbvie, Agios, Calithera, Cleave, BMS/Celgene, Daiichi-Sankyo, Forma, ImmuneOnc, Loxo, and received consultancy or advisory board fees from AbbVie, Agios, Novartis, Agios, Aprea, Celgene/BMS, ImmuneOnc, Notable Laboratories, and Takeda. E.J. received research funding from Abbvie, Adaptive Biotechnologies, Amgen, Bristol-Myers Squibb, Pfizer and Takeda and received advisory board fees from Genetech. H.M.K. received research funding from Ariad, Astex, Bristol-Myers Squibb, Cyclacel, Daiichi-Sankyo, Pfizer, Immunogen, Jazz, Novartis and honoraria from Pfizer, Immunogen, Actinium and Takeda. M.A. received research funding from Daiichi Sankyo, and consultancy honoraria from Jazz, Celgene, Amgen, AstaZeneca, Dimensions Capital, and equity ownership from Reata, Aptose, Europics, Senti Bio, Chimerix, Oncolyze.

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Issa, G.C., Ravandi, F., DiNardo, C.D. et al. Therapeutic implications of menin inhibition in acute leukemias. Leukemia (2021). https://doi.org/10.1038/s41375-021-01309-y

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