期刊
BLOOD
卷 124, 期 26, 页码 3939-3946出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2014-09-601567
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资金
- Cancer Council of Victoria
- Sydney Parker Smith postdoctoral research fellowship
- Sydney Parker Smith postgraduate research scholarship
- Lady Tata Memorial Trust
- National Health and Medical Research Council [1016701, 1020363]
- Leukemia and Lymphoma Society [7001-03]
- University of Melbourne International Research Scholarship
- University of Melbourne International Fee Remission scholarship
- Australian Postgraduate award
- Cancer Therapeutics CRC Top-up scholarship
- Australian Government Independent Research Institutes Infrastructure Support Scheme
- Victorian State Government Operational Infrastructure Support
Apoptosis plays a role in normal lymphopoiesis and lymphoid malignancies. Pro-survival MCL-1 is essential for survival of T-cell progenitors, BCL-XL for immature thymocytes, and BCL-2 for mature T cells. Conversely, little is known about the regulators that are required for the survival of T-cell lymphomas. We used constitutive and conditionally gene-targeted mice to investigate which pro-survival BCL-2 family member is required for the sustained survival of thymic lymphomas initiated by loss of p53. Constitutive loss of a single Mcl-1 allele delayed tumor onset. In contrast, lymphomas emerging in p53(-/-) mice in which Mcl-1 could be conditionally deleted had been selected for retention of MCL-1 expression. In contrast, complete loss of BCL-XL had no impact on lymphoma development in p53(-/-) mice. These results demonstrate that thymic lymphomas elicited by loss of p53 must arise from cancer-initiating cells that require MCL-1 for their survival. Acute deletion of both Mcl-1 alleles abrogated the expansion of p53(-/-) lymphomas in mice, whereas inducible loss of BCL-XL had little impact. This reveals that MCL-1 is essential for the sustained survival of these malignant cells and suggests that targeting MCL-1 may be an attractive strategy for the treatment of T-cell lymphoma.
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