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ASH 2024 | The mechanism and potential of menin inhibitors in NMP1-mutated and KMT2A-rearranged AML
Harry Erba, MD, PhD, Duke University, Durham, NC, comments on the value of menin inhibitors in treating acute myeloid leukemia (AML). Dr Erba explains the mechanism of action of these agents in NPM1-mutated and KMT2A-rearranged AML and discusses how they have the potential to improve outcomes for these patients with unmet clinical needs. This interview took place at the 66th ASH Annual Meeting and Exposition, held in San Diego, CA.
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Transcript
Menin is a scaffolding protein that’s involved in transcriptional regulation of gene expression in myeloid cells. And what we know is that it interacts with KMT2A, used to be known as MLL, and that interaction can lead to an upregulation of HOXA9 and other HOX genes, MEIS1, which creates a kind of leukemogenic phenotype in terms of gene expression for those cells. Menin inhibitors are able to interfere with the binding of KMT2A with menin or KMT2A fusion proteins with menin and block that interaction leading to downregulation of HOX genes MEIS1 and thereby allowing differentiation...
Menin is a scaffolding protein that’s involved in transcriptional regulation of gene expression in myeloid cells. And what we know is that it interacts with KMT2A, used to be known as MLL, and that interaction can lead to an upregulation of HOXA9 and other HOX genes, MEIS1, which creates a kind of leukemogenic phenotype in terms of gene expression for those cells. Menin inhibitors are able to interfere with the binding of KMT2A with menin or KMT2A fusion proteins with menin and block that interaction leading to downregulation of HOX genes MEIS1 and thereby allowing differentiation. In terms of NPM1, what we now know is NPM1 in concert with the nuclear export protein XPO1 will cause menin to drive transcription of genes that are leukemogenic. And so by blocking that interaction again, you can overcome that impact of the NPM1 mutation. NPM1 mutations occur in about 30% of AML patients. Although their outcomes are generally more favorable, we know that not all patients will be cured with intensive chemotherapy. Some may require a transplant. And so I think there’s still an unmet need for this group of patients, especially at the time of relapse. For KMT2A, although those rearrangements are associated with very high remission rates with intensive chemotherapy, the relapse rates are very high. And so I think we need to think about using other drugs that might be able to target the biology of NPM1 mutated and KMT2A rearranged. And that’s where the menin inhibitors come in. And at this year’s Congress, we had an oral session that had data from four of those menin inhibitors in development.
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Disclosures
Stemline: Consultancy, Other: Advisory Board/Consultant; Servier: Consultancy, Other: Advisory Board/Consultant, Research Funding, Speakers Bureau; Schrodinger: Consultancy, Other: Advisory Board/Consultant; Pfizer: Consultancy, Other: Advisory Board/Consultant; Novartis: Consultancy, Other: Advisory Board/Consultant, Research Funding, Speakers Bureau; Macrogenics: Consultancy, Other: Advisory Board/Consultant, Research Funding; Kura Oncology: Consultancy, Other: Advisory Board/Consultant, Research Funding; Jazz: Consultancy, Other: Advisory Board/Consultant, Speakers Bureau; Incyte: Consultancy, Other: Advisory Board/Consultant; Immunogen: Consultancy, Other: Advisory Board/Consultant; Glycomimetics: Consultancy, Other: Advisory Board; Steering Committee member, Research Funding; Genentech: Consultancy, Other: Advisory Board; Daiichi Sankyo: Consultancy, Other, Research Funding; Celgene: Consultancy, Other: Advisory Board; Chair, Myeloid Neoplasms Repository Study., Research Funding, Speakers Bureau; BMS: Consultancy, Other: Advisory Board; Chair, Myeloid Neoplasms Repository Study., Speakers Bureau; Astellas: Consultancy, Other: Advisory Board; Agios: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Consultancy, Honoraria, Other: Chair, Independent Review Committee for VIALE A and VIALE C, Research Funding; Sumitomo Pharma: Consultancy, Other: Advisory Board/Consultant, Research Funding; Syros: Consultancy, Other: Advisory Board/Consultant; Takeda: Consultancy, Other: Advisory Board/Consultant; Trillium: Consultancy, Other: Advisory Board/Consultant; ALX Oncology: Research Funding; Aptose: Research Funding; Ascentage: Research Funding; Oryzon: Research Funding; PTE: Research Funding; Taiho Oncology: Research Funding.
