MNT: a new target for AML

Fischer, KC; Litalien, V; Diepstraten, ST; Jahja, M; Brown, FC; Kelly, GL; Wei, AH; Cory, S

Author(s): Fischer, KC; Litalien, V; Diepstraten, ST; Jahja, M; Brown, FC; Kelly, GL; Wei, AH; Cory, S;
Details: Publication Year 2025-11,Volume 2,Issue #4,Page 100149
Journal Title: Blood Neoplasia
Publication Type: Research article
Abstract: 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-X(L) (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.
Publisher: American Society of Hematology
Department(s): Haematology
Publisher's Version: https://doi.org/10.1016/j.bneo.2025.100149
Open Access at Publisher's Site: https://doi.org/10.1016/j.bneo.2025.100149
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2025-11-11 04:09:26

Last Modified: 2025-11-11 04:09:46