Endogenous bcl-2 is not required for the development of Emu-myc-induced B-cell lymphoma.
Although myc and bcl-2 synergize in tumor development, particularly lymphomagenesis, it is not known whether endogenous bcl-2 is required for myc-induced tumorigenesis. To investigate the role of endogenous Bcl-2 in myc-induced lymphomagenesis, we bypassed the early death of Bcl-2-deficient mice by reconstituting lethally irradiated wild-type (wt) mice with a hematopoietic system from fetal liver-derived stem cells of Emu-myc/bcl-2(-/-) or control Emu-myc transgenic embryos. In premalignant (healthy) recipients, loss of Bcl-2 caused a moderate decrease in pre-B and immature B cells, and a dramatic reduction of mature B lymphocytes expressing the Emu-myc transgene. Furthermore, cultured preneoplastic Emu-myc/bcl-2(-/-) mature B cells displayed accelerated apoptosis compared with Emu-myc B cells. However, despite the striking reduction in B-cell numbers in vivo, ablation of endogenous Bcl-2 did not prevent or even delay development of Emu-myc lymphoma. Moribund mice presented with similar degrees of splenomegaly, blood leukocyte numbers, and tumor dissemination at death. These findings demonstrate that the initiation, development, continued growth, and severity of Emu-myc lymphoma do not depend upon endogenous Bcl-2, nor upon the total number of B lymphoid cells driven by the Emu-myc transgene. These results have implications for the treatment of hematopoietic tumors, particularly those that are not caused by Bcl-2 overexpression.
Kelly
Priscilla N
PN
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3050 Victoria, Melbourne, Australia.
Puthalakath
Hamsa
H
Adams
Jerry M
JM
Strasser
Andreas
A
D000818:Animals; D017209:Apoptosis; D016923:Cell Death; D002469:Cell Separation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D007962:Leukocytes / Q000166:cytology; D016393:Lymphoma, B-Cell / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism / Q000502:physiology*; D016271:Proto-Oncogene Proteins c-myc / Q000502:physiology*; D013997:Time Factors
D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc