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

Stephanie Grabow; Alex R D Delbridge; Brandon J Aubrey; Cassandra J Vandenberg; Andreas Strasser

doi:10.1016/j.celrep.2016.02.039

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

Cell Rep. 2016 Mar 15;14(10):2337-47. doi: 10.1016/j.celrep.2016.02.039. Epub 2016 Mar 3.

Authors

Stephanie Grabow¹, Alex R D Delbridge², Brandon J Aubrey³, Cassandra J Vandenberg², Andreas Strasser⁴

Affiliations

¹ The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; The Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia. Electronic address: grabow@wehi.edu.au.
² The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; The Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia.
³ The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; The Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia; Department of Clinical Haematology and Bone Marrow Transplant Service, the Royal Melbourne Hospital, Melbourne, VIC 3050, Australia.
⁴ The Walter and Eliza Hall Institute of Medical Research, Melbourne, VIC 3052, Australia; The Department of Medical Biology, University of Melbourne, Melbourne, VIC 3010, Australia. Electronic address: strasser@wehi.edu.au.

PMID: 26947081
DOI: 10.1016/j.celrep.2016.02.039

Abstract

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.

Keywords: BIM; MCL-1; MYC; apoptosis; lymphoma; p53.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alleles
Animals
Apoptosis Regulatory Proteins / genetics
Apoptosis Regulatory Proteins / metabolism
Apoptosis*
Bcl-2-Like Protein 11 / genetics
Bcl-2-Like Protein 11 / metabolism
Bone Marrow / metabolism
Bone Marrow / pathology
Flow Cytometry
Genotype
Kaplan-Meier Estimate
Lymphoma / mortality
Lymphoma / pathology
Lymphoma / physiopathology*
Mice
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Myeloid Cell Leukemia Sequence 1 Protein / antagonists & inhibitors
Myeloid Cell Leukemia Sequence 1 Protein / genetics
Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
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

Substances

Apoptosis Regulatory Proteins
Bcl-2-Like Protein 11
Mcl1 protein, mouse
Myeloid Cell Leukemia Sequence 1 Protein
PUMA protein, mouse
Proto-Oncogene Proteins c-myc
Tumor Suppressor Protein p53
Tumor Suppressor Proteins