Although intrinsic apoptosis defects are causal to the extended survival of chronic lymphocytic leukemia (CLL) B cells, several lines of evidence support a contribution of the peripheral lymphoid organs and BM microenvironment to the extended lifespan of leukemic B cells. Lymphocyte trafficking is controlled by homing signals provided by stromal cell-derived chemokines and egress signals provided by sphingosine-1-phosphate (S1P). In the present study, we show that expression of S1P1, the S1P receptor responsible for lymphocyte egress, is selectively reduced in CLL B cells with unmutated IGHV. Expression of S1P2, which controls B-cell homeostasis, is also impaired in CLL B cells but independently of the IGHV mutational status. We provide evidence herein that p66Shc, a Shc adaptor family member the deficiency of which is implicated in the apoptosis defects of CLL B cells, controls S1P1 expression through its pro-oxidant activity. p66Shc also controls the expression of the homing receptor CCR7, which opposes S1P1 by promoting lymphocyte retention in peripheral lymphoid organs. The results of the present study provide insights into the regulation of S1P1 expression in B cells and suggest that defective egress caused by impaired S1P1 expression contributes to the extended survival of CLL B cells by prolonging their residency in the prosurvival niche of peripheral lymphoid organs.

译文

尽管固有的凋亡缺陷是慢性淋巴细胞性白血病 (CLL) b细胞延长存活的原因,但有几条证据支持外周淋巴器官和BM微环境对白血病b细胞延长寿命的贡献。淋巴细胞运输由基质细胞衍生的趋化因子提供的归巢信号和由sphingosine-1-phosphate (S1P) 提供的出口信号控制。在本研究中,我们表明,在未突变的IGHV的CLL b细胞中,负责淋巴细胞流出的S1P受体S1P1的表达选择性降低。控制b细胞稳态的S1P2的表达在CLL b细胞中也受到损害,但与IGHV突变状态无关。我们在此提供的证据表明,p66Shc是Shc衔接子家族成员,其缺陷与CLL b细胞的凋亡缺陷有关,它通过其促氧化剂活性控制S1P1的表达。p66Shc还控制归巢受体CCR7的表达,该受体通过促进淋巴细胞在周围淋巴器官中的保留来对抗S1P1。本研究的结果提供了对b细胞中S1P1表达调控的见解,并表明由S1P1表达受损引起的缺陷出口通过延长CLL b细胞在周围淋巴器官的生存状态而有助于延长CLL b细胞的存活。

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