Journal
BLOOD
Volume 109, Issue 11, Pages 4907-4913Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2006-10-051847
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Funding
- NCI NIH HHS [CA 80188, R01 CA043540, CA 43540, R01 CA080188] Funding Source: Medline
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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 E mu-mycl bcl-2(-/-) or control E mu-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 E mu-myc transgene. Furthermore, cultured preneoplastic E mu-myc/bcl-2(-1-) mature B cells displayed accelerated apoptosis compared with E mu-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 E mu-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 E mu-myc lymphoma do not depend upon endogenous Bcl-2, nor upon the total number of B lymphoid cells driven by the E mu-myc transgene. These results have implications for the treatment of hematopoietic tumors, particularly those that are not caused by Bcl-2 overexpression.
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