MNT: a new target for AML

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 <i>Mnt-</i>deletable murine <i>MLL::AF9</i> acute myeloid leukemias (AMLs), using the well-studied hemopoietic reconstitution model. <i>Mnt</i> deletion provoked the apoptosis of <i>MLL::AF9</i> 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-X_L (B-cell lymphoma-extra large) specific). Remarkably, by inducing <i>Mnt</i> deletion in vivo in transplanted <i>MLL::AF9</i> AMLs, we significantly extended the survival of transplant recipients (<i>P</i> < .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 <i>MNT</i> deletion. Of note, inducing <i>MNT</i> deletion in a human <i>MLL-</i>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.