Journal Article

Therapeutic implications of menin inhibition in acute leukemias

DiNardo, Courtney D., Andreeff, Michael, Jabbour, Elias, Kantarjian, Hagop M., Issa, Ghayas C., Ravandi, Farhad

2021

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 45/23 / 631/67/1990/283 / 692/308/153 / Acute myeloid leukemia / Antineoplastic Agents - pharmacology / Cancer Research / Care and treatment / Critical Care Medicine / Development and progression / Endocrine glands / Epigenetics / Gene mutations / Gene rearrangement / Gene regulation / Genetic aspects / Health aspects / Hematology / Humans / Inhibitors / Intensive / Internal Medicine / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - pathology / Leukemogenesis / Lysine / Medicine / Medicine & Public Health / Methyltransferase / Molecular Targeted Therapy / Multiple endocrine neoplasia / Mutation / Myeloid leukemia / Neuroendocrine tumors / Nucleophosmin / Oncology / Proto-Oncogene Proteins - antagonists & inhibitors / Review Article / Transcription / Tumor suppressor genes / Tumors