Chronic lymphocytic leukemia of Eμ-TCL1 transgenic mice undergoes rapid cell turnover that can be offset by extrinsic CD257 to accelerate disease progression
Chronic lymphocytic leukemia of Eμ-TCL1 transgenic mice undergoes rapid cell turnover that can be offset by extrinsic CD257 to accelerate disease progression
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DOI：
10.1182/blood-2009-06-230169
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发表时间：
2009-11-12
期刊：
影响因子：
20.3
通讯作者：
Kipps, Thomas J.
中科院分区：
文献类型：
--
作者：
Enzler, Thomas;Kater, Arnon P.;Kipps, Thomas J.
重水标记研究的结果挑战了慢性淋巴细胞白血病（CLL）代表非循环B细胞积累的观念。我们检测了E mu-TCL1转基因（TCL1-Tg）小鼠的白血病细胞周转，这些小鼠在8至12月龄时发生cll样疾病。我们发现，与非白血病淋巴细胞相比，白血病细胞不仅有更高比例的增殖细胞，而且有更高比例的凋亡细胞。我们将TCL1-Tg与表达高水平CD257的BAFF-Tg小鼠杂交。与TCL1-Tg小鼠相比，TCL1xBAFF-Tg小鼠发生cll样疾病的年龄明显更小，疾病进展更快，生存期更短。TCL1xBAFF-Tg小鼠白血病细胞的增殖细胞比例与TCL1-Tg小鼠相似，但死亡细胞比例低于TCL1-Tg小鼠。此外，来自TCL1xBAFF-Tg或TCL1-Tg小鼠的白血病细胞在转移到BAFF-Tg小鼠体内时比转移到野生型（WT）小鼠体内时产生更强的侵袭性疾病。CD257的中和导致循环白血病细胞的快速减少。这些结果表明，TCL1-Tg小鼠的白血病细胞经历了高水平的自发凋亡，这被相对较高的白血病细胞增殖率所抵消，这可能允许获得有助于疾病进化的突变。(血。2009;114:4469 - 4476)
Results of heavy-water labeling studies have challenged the notion that chronic lymphocytic leukemia (CLL) represents an accumulation of noncycling B cells. We examined leukemia cell turnover in E mu-TCL1 transgenic (TCL1-Tg) mice, which develop a CLL-like disease at 8 to 12 months of age. We found that leukemia cells in these mice not only had higher proportions of proliferating cells but also apoptotic cells than did nonleukemic lymphocytes. We crossed TCL1-Tg with BAFF-Tg mice, which express high levels of CD257. TCL1xBAFF-Tg mice developed CLL-like disease at a significantly younger age and had more rapid disease progression and shorter survival than TCL1-Tg mice. Leukemia cells of TCL1xBAFF-Tg mice had similar proportions of proliferating cells, but fewer proportions of dying cells, than did the CLL cells of TCL1-Tg mice. Moreover, leukemia cells from either TCL1xBAFF-Tg or TCL1-Tg mice produced more aggressive disease when transferred into BAFF-Tg mice than into wild-type (WT) mice. Neutralization of CD257 resulted in rapid reduction in circulating leukemia cells. These results indicate that the leukemia cells of TCL1-Tg mice undergo high levels of spontaneous apoptosis that is offset by relatively high rates of leukemia cell proliferation, which might allow for acquisition of mutations that contribute to disease evolution. (Blood. 2009;114:4469-4476)