# MNT: a new target for AML

## TL;DR

This study shows that inhibiting MNT, a protein related to MYC, can improve treatment for certain types of leukemia in mice.

## Contribution

The study is the first to show that MNT is a potential therapeutic target in MLL-driven AML.

## Key findings

- Deleting MNT in MLL::AF9 AML cells increases apoptosis and extends survival in mice.
- MNT inhibition enhances the effectiveness of BH3 mimetic drugs in AML cell lines.
- MNT inhibition debulks established leukemia in human cell transplants in mice.

## Abstract

•Inducing MNT loss in AMLs driven by MLL-fusion proteins extends survival of transplanted mice, indicative of MNT-dependency.•Inhibiting MNT, a MYC family member, may therefore improve therapy for MLL-driven and perhaps also other AMLs.

Inducing MNT loss in AMLs driven by MLL-fusion proteins extends survival of transplanted mice, indicative of MNT-dependency.

Inhibiting MNT, a MYC family member, may therefore improve therapy for MLL-driven and perhaps also other AMLs.

Deregulated expression of the transcription factor c-MYC is well established as a primary driver of diverse tumor types. In this study, for the first time to our knowledge, we show that mouse and human myeloid leukemias provoked by oncogenic mixed lineage leukemia (MLL) fusion proteins are dependent on the MYC family member MNT (MAX network transcriptional repressor), which is highly expressed in these AMLs. To investigate the role of MNT, we generated Mnt-deletable murine MLL::AF9 acute myeloid leukemias (AMLs), using the well-studied hemopoietic reconstitution model. Mnt deletion provoked the apoptosis of MLL::AF9 AML cells in vitro and increased apoptosis elicited by the BH3 (BCL-2 homology region 3) mimetic drugs S63845 (MCL-1 (Myeloid cell leukemia-1) specific), ABT-199/Venetoclax (BCL-2 (B-cell lymphoma-2) specific), and A-1331852 (BCL-XL (B-cell lymphoma-extra large) specific). Remarkably, by inducing Mnt deletion in vivo in transplanted MLL::AF9 AMLs, we significantly extended the survival of transplant recipients (P < .0001), 50% of which became leukemia free. Using inducible CRISPR/Cas9, we also showed that 3 of 4 human AML cell lines were more potently killed in vitro by BH3 mimetic drugs after MNT deletion. Of note, inducing MNT deletion in a human MLL-rearranged AML cell line transplanted into NSG (NOD SCID Gamma) mice debulked established leukemia and significantly extended the survival of transplant recipients. Taken together with previous studies that demonstrated a critical role for MNT in the development and sustained expansion of B and T lymphomas, our results suggest that a small molecule inhibiting MNT function may be a valuable therapeutic agent for myeloid and lymphoid malignancies.