Critical B-lymphoid cell intrinsic role of endogenous MCL-1 in c-MYC-induced lymphomagenesis
AuthorGrabow, S; Kelly, GL; Delbridge, ARD; Kelly, PN; Bouillet, P; Adams, JM; Strasser, A
Source TitleCell Death and Disease
PublisherNATURE PUBLISHING GROUP
University of Melbourne Author/sBouillet, Philippe; Grabow, Stephanie; Delbridge, Alex; Kelly, Gemma; Strasser, Andreas; Adams, Jerry
AffiliationMedical Biology (W.E.H.I.)
Document TypeJournal Article
CitationsGrabow, S., Kelly, G. L., Delbridge, A. R. D., Kelly, P. N., Bouillet, P., Adams, J. M. & Strasser, A. (2016). Critical B-lymphoid cell intrinsic role of endogenous MCL-1 in c-MYC-induced lymphomagenesis. CELL DEATH & DISEASE, 7 (3), https://doi.org/10.1038/cddis.2016.43.
Access StatusOpen Access
Evasion of apoptosis is critical for tumorigenesis, and sustained survival of nascent neoplastic cells may depend upon the endogenous levels of pro-survival BCL-2 family members. Indeed, previous studies using gene-targeted mice revealed that BCL-XL, but surprisingly not BCL-2, is critical for the development of c-MYC-induced pre-B/B lymphomas. However, it remains unclear whether another pro-survival BCL-2 relative contributes to their development. MCL-1 is an intriguing candidate, because it is required for cell survival during early B-lymphocyte differentiation. It is expressed abnormally high in several types of human B-cell lymphomas and is implicated in their resistance to chemotherapy. To test the B-cell intrinsic requirement for endogenous MCL-1 in lymphoma development, we conditionally deleted Mcl-1 in B-lymphoid cells of Eμ-Myc transgenic mice. We found that MCL-1 loss in early B-lymphoid progenitors delayed MYC-driven lymphomagenesis. Moreover, the lymphomas that arose when MCL-1 levels were diminished appeared to have been selected for reduced levels of BIM and/or increased levels of BCL-XL. These results underscore the importance of MCL-1 in lymphoma development and show that alterations in the levels of other cell death regulators can compensate for deficiencies in MCL-1 expression.
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