[PDF][PDF] Loss of a single Mcl-1 allele inhibits MYC-driven lymphomagenesis by sensitizing pro-B cells to apoptosis

S Grabow, ARD Delbridge, BJ Aubrey, CJ Vandenberg… - Cell reports, 2016 - cell.com
Cell reports, 2016cell.com
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 …
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.
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