Cell Reports
Volume 14, Issue 10, 15 March 2016, Pages 2337-2347
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Article
Loss of a Single Mcl-1 Allele Inhibits MYC-Driven Lymphomagenesis by Sensitizing Pro-B Cells to Apoptosis

https://doi.org/10.1016/j.celrep.2016.02.039Get rights and content
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Highlights

  • Loss of one Mcl-1 allele substantially delays lymphomagenesis

  • MCL-1 antagonizes BIM in lymphoma development

  • Loss of p53 reduces requirement for MCL-1 during lymphomagenesis

Summary

MCL-1 is critical for progenitor cell survival during emergency hematopoiesis, but its role in sustaining cells undergoing transformation and in lymphomagenesis is only poorly understood. We investigated the importance of MCL-1 in the survival of B lymphoid progenitors undergoing MYC-driven transformation and its functional interactions with pro-apoptotic BIM and PUMA and the tumor suppressor p53 in lymphoma development. Loss of one Mcl-1 allele almost abrogated MYC-driven-lymphoma development owing to a reduction in lymphoma initiating pre-B cells. Although loss of the p53 target PUMA had minor impact, loss of one p53 allele substantially accelerated lymphoma development when MCL-1 was limiting, most likely because p53 loss also causes defects in non-apoptotic tumor suppressive processes. Remarkably, loss of BIM restored the survival of lymphoma initiating cells and rate of tumor development. Thus, MCL-1 has a major role in lymphoma initiating pro-B cells to oppose BIM, which is upregulated in response to oncogenic stress.

Keywords

MCL-1
MYC
p53
BIM
apoptosis
lymphoma

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This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).