MCL-1 but not BCL-XL is critical for the development and sustained expansion of thymic lymphoma in p53-deficient mice

• Published in: Blood 2014-12, Vol.124 (26), p.3939-3946
• Main Authors: Grabow, Stephanie, Delbridge, AlexR. D., Valente, Liz J., Strasser, Andreas
• Format: Article
• Language: English
• Subjects: Alleles; Animals; Apoptosis; bcl-X Protein - genetics; bcl-X Protein - physiology; Cell Survival; Cell Transplantation; Gene Deletion; Gene Expression Regulation, Neoplastic; Genes, p53; Genotype; Lymphoma, T-Cell - metabolism; Mice; Mice, Inbred C57BL; Mutation; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - physiology; Stem Cells - cytology; Thymus Neoplasms - metabolism
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2014-09-601567

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. •MCL-1 is critical for thymic lymphoma development mediated by loss of p53.•MCL-1 is essential for sustained growth of p53-deficient thymic lymphoma cells.