Loss of a Single Mcl-1 Allele Inhibits MYC-Driven Lymphomagenesis by Sensitizing Pro-B Cells to Apoptosis

• Published in: Cell reports (Cambridge) 2016-03, Vol.14 (10), p.2337-2347
• Main Authors: Grabow, Stephanie, Delbridge, Alex R.D., Aubrey, Brandon J., Vandenberg, Cassandra J., Strasser, Andreas
• Format: Article
• Language: English
• Subjects: Alleles; Animals; Apoptosis; Apoptosis Regulatory Proteins - genetics; Apoptosis Regulatory Proteins - metabolism; Bcl-2-Like Protein 11 - genetics; Bcl-2-Like Protein 11 - metabolism; BIM; Bone Marrow - metabolism; Bone Marrow - pathology; Flow Cytometry; Genotype; Kaplan-Meier Estimate; lymphoma; Lymphoma - mortality; Lymphoma - pathology; Lymphoma - physiopathology; MCL-1; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; MYC; Myeloid Cell Leukemia Sequence 1 Protein - antagonists & inhibitors; Myeloid Cell Leukemia Sequence 1 Protein - genetics; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; p53; Precursor Cells, B-Lymphoid - cytology; Precursor Cells, B-Lymphoid - metabolism; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Real-Time Polymerase Chain Reaction; Sequence Analysis, DNA; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.02.039

MCL-1 is critical for progenitor cell survival during emergency hematopoiesis, but its role in sustaining cells undergoing transformation and in lymphomagenesis is only poorly understood. We investigated the importance of MCL-1 in the survival of B lymphoid progenitors undergoing MYC-driven transformation and its functional interactions with pro-apoptotic BIM and PUMA and the tumor suppressor p53 in lymphoma development. Loss of one Mcl-1 allele almost abrogated MYC-driven-lymphoma development owing to a reduction in lymphoma initiating pre-B cells. Although loss of the p53 target PUMA had minor impact, loss of one p53 allele substantially accelerated lymphoma development when MCL-1 was limiting, most likely because p53 loss also causes defects in non-apoptotic tumor suppressive processes. Remarkably, loss of BIM restored the survival of lymphoma initiating cells and rate of tumor development. Thus, MCL-1 has a major role in lymphoma initiating pro-B cells to oppose BIM, which is upregulated in response to oncogenic stress. [Display omitted] •Loss of one Mcl-1 allele substantially delays lymphomagenesis•MCL-1 antagonizes BIM in lymphoma development•Loss of p53 reduces requirement for MCL-1 during lymphomagenesis MCL-1 is overexpressed in various human cancers. Grabow et al. reveal the importance of MCL-1 for the survival of B cell progenitors undergoing neoplastic transformation and in lymphomagenesis. Given that non-transformed cells appear to be less dependent on MCL-1 than malignant ones, inhibitors of MCL-1 may be useful in cancer therapy.