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Development and Survival of MYC-driven Lymphomas Requires MYC-Antagonist MNT to Curb MYC-induced Apoptosis

Deregulated over-expression of MYC is implicated in the development and malignant progression of most (~70%) human tumors. MYC drives cell growth and proliferation but also, at high levels, promotes apoptosis. Here, we report that the proliferative capacity of MYC-driven normal and neoplastic B lymp...

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Bibliographic Details
Published in:Blood 2020-01
Main Authors: Nguyen, Hai Vu, Vandenberg, Cassandra J, Ng, Ashley P, Robati, Mikara R, Anstee, Natasha S, Rimes, Joel, Hawkins, Edwin, Cory, Suzanne
Format: Article
Language:English
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Summary:Deregulated over-expression of MYC is implicated in the development and malignant progression of most (~70%) human tumors. MYC drives cell growth and proliferation but also, at high levels, promotes apoptosis. Here, we report that the proliferative capacity of MYC-driven normal and neoplastic B lymphoid cells depends on MNT, a MYC-related transcriptional repressor. Our genetic data establish that MNT synergises with MYC by suppressing MYC-driven apoptosis and that it does so primarily by reducing the level of pro-apoptotic BIM. In Em-Myc mice, which model the MYC/IGH chromosome translocation in Burkitt's lymphoma, homozygous Mnt deletion greatly reduced lymphoma incidence by enhancing apoptosis and markedly decreasing premalignant B lymphoid cell populations. Strikingly, by inducing Mnt deletion within transplanted fully-malignant Em-Myc lymphoma cells, we significantly extended transplant recipient survival. The dependency of lymphomas on MNT for survival suggests that drugs inhibiting MNT could significantly boost therapy of MYC-driven tumors by enhancing intrinsic MYC-driven apoptosis.
ISSN:0006-4971
1528-0020
DOI:10.1182/blood.2019003014