Loss of a Single Mcl-1 Allele Inhibits MYC-Driven Lymphomagenesis by Sensitizing Pro-B Cells to Apoptosis

Publication date: Available online 3 March 2016
Source:Cell Reports
Author(s): Stephanie Grabow, Alex R.D. Delbridge, Brandon J. Aubrey, Cassandra J. Vandenberg, Andreas Strasser
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.

Graphical abstract

Teaser

MCL-1 is overexpressed in various human cancers. Grabow et al. reveal the importance of MCL-1 for the survival of B cell progenitors undergoing neoplastic transformation and in lymphomagenesis. Given that non-transformed cells appear to be less dependent on MCL-1 than malignant ones, inhibitors of MCL-1 may be useful in cancer therapy.


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