Development and survival of MYC-driven lymphomas require the MYC antagonist MNT to curb MYC-induced apoptosis

Hai Vu Nguyen, Cassandra J Vandenberg, Ashley P. Ng, Mikara Robati, Natasha Anstee, Joel Rimes, Edwin D. Hawkins, Suzanne Cory

Research output: Contribution to journalArticleResearchpeer-review

5 Citations (Scopus)

Abstract

Deregulated overexpression 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 synergizes with MYC by suppressing MYC-driven apoptosis, and that it does so primarily by reducing the level of pro-apoptotic BIM. In Eμ-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 Eμ-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.

Original languageEnglish
Pages (from-to)1019-1031
Number of pages13
JournalBlood
Volume135
Issue number13
DOIs
Publication statusPublished - 26 Mar 2020
Externally publishedYes

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