MNT: a new target for AML.

Area of Science:

• Oncology
• Molecular Biology
• Hematology

Background:

• Deregulated c-MYC expression is a known driver of various cancers.
• Myeloid leukemias involving mixed lineage leukemia (MLL) fusion proteins are a significant clinical challenge.
• The role of the MYC family member MNT (MAX network transcriptional repressor) in MLL-driven leukemias was previously unexplored.

Purpose of the Study:

• To investigate the dependency of MLL-driven myeloid leukemias on MNT.
• To evaluate the therapeutic potential of targeting MNT in acute myeloid leukemia (AML).

Main Methods:

• Generation of Mnt-deletable murine MLL::AF9 acute myeloid leukemias (AMLs) using a hemopoietic reconstitution model.
• Assessment of Mnt deletion effects on AML cell apoptosis in vitro, including responses to BH3 mimetic drugs.
• In vivo studies involving Mnt deletion in transplanted murine and human AML models (including NSG mice) and CRISPR/Cas9 gene editing in human AML cell lines.

Main Results:

• Mnt deletion induced apoptosis in MLL::AF9 AML cells in vitro and sensitized them to BH3 mimetic drugs.
• In vivo Mnt deletion significantly extended survival in mice with MLL::AF9 AML, with 50% achieving leukemia-free status.
• MNT deletion enhanced the efficacy of BH3 mimetic drugs against human AML cell lines and reduced leukemia burden in vivo.

Conclusions:

• MLL-driven myeloid leukemias are dependent on MNT.
• MNT deletion represents a promising therapeutic strategy for AML, enhancing sensitivity to existing drugs.
• Targeting MNT function with small molecules could offer a novel therapeutic approach for both myeloid and lymphoid malignancies.