MNT: a new target for AML

Le résumé fourni par la source

Deregulated expression of the transcription factor c-MYC is well-established as a primary driver of diverse tumour types. Here, for the first time, we show that mouse and human myeloid leukaemias provoked by oncogenic MLL (mixed lineage leukaemia) fusion proteins are dependent on the MYC family member MNT, which is highly expressed in these AMLs. To investigate the role of MNT, we generated Mnt- deletable murine MLL-AF9 acute myeloid leukaemias (AMLs), using the well-studied haemopoietic reconstitution model. Mnt deletion provoked apoptosis of MLL-AF9 AML cells in vitro and increased apoptosis elicited by BH3 mimetic drugs S63845 (MCL-1-specific), ABT-199/Venetoclax (BCL-2-specific) and A-1331852 (BCL-X L -specific). Remarkably, by inducing Mnt deletion in vivo in transplanted MLL-AF9 AMLs, we significantly extended survival of transplant recipients (p<0.0001), 50% of which became leukaemia-free. Using inducible CRISPR/Cas9, we also showed that three of four 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-r AML cell line transplanted into NGS mice debulked established leukaemia and significantly extended the survival of transplant recipients. Taken together with previous studies demonstrating 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 for myeloid as well as lymphoid malignancies.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.