Brandvold K A, Ewert D L, Kent S C, Neiman P, Ruddell A
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109-1024, USA.
Oncogene. 2001 May 31;20(25):3226-34. doi: 10.1038/sj.onc.1204431.
Avian leukosis virus induces lymphoma in chickens after proviral integration within the c-Myc gene, and subsequent expansion of Myc-overexpressing lymphocytes within transformed bursal follicles. The clonal expansion of these follicles allowed us to examine how Myc influences cell differentiation, growth, and apoptosis in lymphoid progenitors soon after the onset of Myc overexpression. Immunohistochemical analysis of developmental markers established that Myc overexpression consistently blocks lymphocyte differentiation at a late embryonic stage. Myc-transformed follicles also grow much more rapidly than normal follicles. This rapid growth is not mediated by suppression of apoptosis, as normal and Myc-transformed follicles showed similar rates of cell death by TUNEL immunohistochemical analysis of cells undergoing DNA degradation. Measurements of DNA synthesis and mitotic index showed modest effects of Myc to increase lymphocyte proliferation, as normal lymphocytes already divide rapidly. The major mechanism mediating rapid growth of transformed follicles instead involved failure of myc-overexpressing lymphocytes to emigrate from transformed follicles, while normal lymphocytes actively emigrate after hatching, as measured by BrdU pulse-chase labeling and immunohistochemical measurements. This failure to undergo the normal program of differentiation and subsequent bursal retention of lymphocytes accounts for most of the growth of transformed follicles, while Myc-induced proliferation makes a smaller contribution.
禽白血病病毒在原病毒整合到c-Myc基因内后，会在鸡体内诱发淋巴瘤，随后在转化的法氏囊滤泡内使Myc过表达的淋巴细胞扩增。这些滤泡的克隆性扩增使我们能够研究Myc在过表达开始后不久如何影响淋巴祖细胞的细胞分化、生长和凋亡。对发育标志物的免疫组织化学分析表明，Myc过表达在胚胎后期持续阻断淋巴细胞分化。Myc转化的滤泡也比正常滤泡生长得快得多。这种快速生长不是由凋亡抑制介导的，因为通过对经历DNA降解的细胞进行TUNEL免疫组织化学分析，正常滤泡和Myc转化的滤泡显示出相似的细胞死亡率。DNA合成和有丝分裂指数的测量表明，Myc对增加淋巴细胞增殖的作用不大，因为正常淋巴细胞已经快速分裂。介导转化滤泡快速生长的主要机制反而涉及Myc过表达的淋巴细胞无法从转化滤泡中迁出，而通过BrdU脉冲追踪标记和免疫组织化学测量发现，正常淋巴细胞在孵化后会积极迁出。淋巴细胞未能经历正常的分化程序并随后在法氏囊中滞留，这是转化滤泡生长的主要原因，而Myc诱导的增殖贡献较小。
