Menin inhibitors for the treatment of acute myeloid leukemia: challenges and opportunities ahead.

Abstract

The AML treatment landscape has significantly changed in recent years with the approval of targeted therapies in the front-line and relapsed/refractory settings, including inhibitors of FLT3 and IDH1/2 mutations.

More importantly, approval of the combination of the BCl-2 inhibitor, venetoclax, and hypomethylating agents or low dose cytarabine provided unprecedented breakthrough for the frontline treatment of older, unfit AML patients.

Even with all this exciting progress, more targeted therapies for AML treatment are needed. Recent development of menin inhibitors targeting AML with KMT2A rearrangements or NPM1 mutations could represent a promising new horizon of treatment for patients within these subsets of AML.

Our current review will focus on a summary and updates of recent developments of menin inhibitors in the treatment of AML, on the challenges ahead arising from drug resistance, as well as on the opportunities of novel combinations with menin inhibitors.

References:

Liu H. Emerging agents and regimens for AML. J Hematol Oncol. 2021;14(1):49.
Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997;276(5311):404–7.
Lemmens I, Van de Ven WJ, Kas K, Zhang CX, Giraud S, Wautot V, Buisson N, De Witte K, Salandre J, Lenoir G, Pugeat M. Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. Human Molecul Gene. 1997;6(7):1177–83.
Murai MJ, Chruszcz M, Reddy G, Grembecka J, Cierpicki T. Crystal structure of menin reveals binding site for mixed lineage leukemia (MLL) protein. J Biol Chem. 2011;286(36):31742–8. 10.1074/jbc.M111.258186.
Huang J, Gurung B, Wan B, Matkar S, Veniaminova NA, Wan K, Merchant JL, Hua X, Lei M. The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature. 2012;482(7386):542–6. 10.1038/nature10806.

Article info

Journal issue:

Volume: 17
Issue: 1

Doi:

10.1186/s13045-024-01632-8

More resources:

BioMed Central

Full Text Sources

Free resource

MedlinePlus Health Information

Medical

Free resource

PubMed Central

Full Text Sources

Free resource

NCI CPTAC Assay Portal

Miscellaneous

Free resource

Menin inhibitors for the treatment of acute myeloid leukemia: challenges and opportunities ahead.

Abstract

References:

Liu H. Emerging agents and regimens for AML. J Hematol Oncol. 2021;14(1):49.
Chandrasekharappa SC, Guru SC, Manickam P, Olufemi SE, Collins FS, Emmert-Buck MR, Debelenko LV, Zhuang Z, Lubensky IA, Liotta LA, Crabtree JS. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997;276(5311):404–7.
Lemmens I, Van de Ven WJ, Kas K, Zhang CX, Giraud S, Wautot V, Buisson N, De Witte K, Salandre J, Lenoir G, Pugeat M. Identification of the multiple endocrine neoplasia type 1 (MEN1) gene. Human Molecul Gene. 1997;6(7):1177–83.
Murai MJ, Chruszcz M, Reddy G, Grembecka J, Cierpicki T. Crystal structure of menin reveals binding site for mixed lineage leukemia (MLL) protein. J Biol Chem. 2011;286(36):31742–8. 10.1074/jbc.M111.258186.
Huang J, Gurung B, Wan B, Matkar S, Veniaminova NA, Wan K, Merchant JL, Hua X, Lei M. The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature. 2012;482(7386):542–6. 10.1038/nature10806.