title: Endogenous Bcl-xL is essential for Myc-driven lymphomagenesis in mice.
abstract: Impaired apoptosis is a cancer hallmark, and some types of lymphomas and other cancers harbor mutations that directly affect key cell death regulators, such as Bcl-2 family members. However, because the majority of tumors seem to lack such mutations, we are examining the hypothesis that tumorigenesis can be sustained at least initially by the normal expression of specific endogenous pro-survival Bcl-2 family members. We previously demonstrated that the lymphomagenesis in Εμ-myc transgenic mice, which constitutively overexpress the c-Myc oncoprotein in B-lymphoid cells and develop pre-B and B-cell lymphomas, does not require endogenous Bcl-2. In striking contrast, we report here that loss in these mice of its close relative Bcl-x(L) attenuated the pre-neoplastic expansion of pro-B and pre-B cells otherwise driven by c-Myc overexpression, sensitized these cells to apoptosis and ablated lymphoma formation. Remarkably, even loss of a single bcl-x allele delayed the lymphomagenesis. These findings identify Bcl-x(L) as a prerequisite for the emergence of c-Myc-driven pre-B/B lymphoma and suggest that BH3 mimetic drugs may provide a prophylactic strategy for c-Myc-driven tumors.
authors: The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia.
authors: Priscilla N
authors: PN
authors: Kelly
authors: Stephanie
authors: S
authors: Grabow
authors: Alex R D
authors: AR
authors: Delbridge
authors: Andreas
authors: A
authors: Strasser
authors: Jerry M
authors: JM
authors: Adams
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002478:Cells, Cultured; D003433:Crosses, Genetic; D005260:Female; D006579:Heterozygote; D016393:Lymphoma, B-Cell / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000378:metabolism / Q000473:pathology; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D016019:Survival Analysis; D015854:Up-Regulation; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: C494812:Bcl2l1 protein, mouse; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D051020:bcl-X Protein