期刊
CELL REPORTS
卷 14, 期 10, 页码 2337-2347出版社
CELL PRESS
DOI: 10.1016/j.celrep.2016.02.039
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资金
- Cancer Council of Victoria
- Lady Tata Memorial Trust
- Leukaemia Foundation Australia
- National Health and Medical Research Council [1016701, 1020363]
- Leukemia and Lymphoma Society (SCOR grant) [7001-03]
- estate of Anthony (Toni) Redstone OAM, University of Melbourne International Research and International Fee Remission Scholarships
- Australian Postgraduate Award
- Leukaemia Foundation National Research Program Clinical PhD Scholarship
- Cancer Therapeutics CRC top-up scholarship
- Australian Government IRIISS
- Victorian State Government OIS
- Genentech
- AbbVie
MCL-1 is critical for progenitor cell survival during emergency hematopoiesis, but its role in sustaining cells undergoing transformation and in lymphoma-genesis 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 proapoptotic 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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