Kelly Priscilla N, Puthalakath Hamsa, Adams Jerry M, Strasser Andreas
Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3050 Victoria, Melbourne, Australia.
Blood. 2007 Jun 1;109(11):4907-13. doi: 10.1182/blood-2006-10-051847. Epub 2007 Feb 22.
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.
尽管myc和bcl-2在肿瘤发生，特别是淋巴瘤发生过程中相互协同作用，但尚不清楚内源性bcl-2是否为myc诱导的肿瘤发生所必需。为了研究内源性Bcl-2在myc诱导的淋巴瘤发生中的作用，我们通过用来自Emu-myc/bcl-2(-/-)或对照Emu-myc转基因胚胎的胎肝来源干细胞的造血系统重建经致死性照射的野生型（wt）小鼠，绕过了Bcl-2缺陷小鼠的早期死亡。在癌前（健康）受体中，Bcl-2的缺失导致前B细胞和未成熟B细胞适度减少，以及表达Emu-myc转基因的成熟B淋巴细胞显著减少。此外，与Emu-myc B细胞相比，培养的癌前Emu-myc/bcl-2(-/-)成熟B细胞显示出加速的细胞凋亡。然而，尽管体内B细胞数量显著减少，但内源性Bcl-2的缺失并未阻止甚至延迟Emu-myc淋巴瘤的发生。濒死小鼠在死亡时出现相似程度的脾肿大、血液白细胞数量和肿瘤扩散。这些发现表明，Emu-myc淋巴瘤的起始、发展、持续生长和严重程度不依赖于内源性Bcl-2，也不依赖于由Emu-myc转基因驱动的B淋巴细胞总数。这些结果对造血系统肿瘤的治疗具有启示意义，特别是那些并非由Bcl-2过表达引起的肿瘤。
