title: MCL-1 but not BCL-XL is critical for the development and sustained expansion of thymic lymphoma in p53-deficient mice.
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, 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.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; and The Department of Medical Biology, University of Melbourne, Melbourne, Australia.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grabow
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; and The Department of Medical Biology, University of Melbourne, Melbourne, Australia.
authors.forename: Alex R D
authors.initials: AR
authors.lastname: Delbridge
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; and The Department of Medical Biology, University of Melbourne, Melbourne, Australia.
authors.forename: Liz J
authors.initials: LJ
authors.lastname: Valente
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia; and The Department of Medical Biology, University of Melbourne, Melbourne, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Strasser
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis; D002470:Cell Survival; D017690:Cell Transplantation; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016158:Genes, p53; D005838:Genotype; D016399:Lymphoma, T-Cell / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000235:genetics / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology; D013953:Thymus Neoplasms / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics / Q000502:physiology*
chemical_list: C494812:Bcl2l1 protein, mouse; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D051020:bcl-X Protein