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

Stephanie Grabow, Alex R.D. Delbridge, Liz J. Valente and Andreas Strasser

Key points

  • 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.

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.

  • Submitted September 17, 2014.
  • Accepted October 22, 2014.