MCL-1 but not BCL-XL is critical for the development and sustained expansion of thymic lymphoma in p53-deficient mice
- Author(s)
- Grabow, S; Delbridge, AR; Valente, LJ; Strasser, A;
- Details
- Publication Year 2014-12-18,Volume 124,Issue #26,Page 3939-46
- Journal Title
- Blood
- Publication Type
- Journal Article
- Abstract
- 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, only 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 and 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.
- Publisher
- ASH
- Keywords
- BCL-2 family ; MCL-1 ; p53 ; apoptosis ; lymphoma ; cancer
- Research Division(s)
- Molecular Genetics Of Cancer
- Publisher's Version
- https://doi.org/10.1182/blood-2014-09-601567
- NHMRC Grants
- NHMRC/1016701, NHMRC/1020363,
- Terms of Use/Rights Notice
- Copyright © 2014 American Society of Hematology.
Creation Date: 2014-11-14 01:51:45
Last Modified: 2014-12-23 11:55:36