Targeting the Menin-KMT2A interaction in leukemia: Lessons learned and future directions

Area of Science:

• Hematology
• Oncology
• Molecular Biology

Background:

• KMT2A rearrangements define a subset of acute leukemias, often linked to poor prognosis.
• Non-rearranged KMT2A complexes also play roles in leukemia development.

Purpose of the Study:

• To review the biology of KMT2A in cancer, focusing on leukemia.
• To provide an overview of clinical and preclinical studies on Menin inhibitors targeting KMT2A.

Main Methods:

• Literature review of KMT2A biology and Menin inhibitor studies.
• Analysis of preclinical models and early-phase clinical trial data.

Main Results:

• KMT2A fusions create oncogenic proteins, while KMT2A complexes are vital in other leukemias.
• Menin-KMT2A inhibitors demonstrate efficacy in preclinical and clinical settings.
• Revumenib, a Menin inhibitor, is approved for KMT2A-rearranged acute leukemia.

Conclusions:

• Targeting the Menin-KMT2A interaction is a viable therapeutic strategy for KMT2A-driven leukemias.
• Understanding resistance mechanisms is crucial for optimizing single-agent or combination therapies.