Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases.
Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases.
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DOI：
10.1084/jem.20091962
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发表时间：
2010-10-25
期刊：
影响因子：
--
通讯作者：
Rickert RC
中科院分区：
文献类型：
--
作者：
Miletic AV;Anzelon-Mills AN;Mills DM;Omori SA;Pedersen IM;Shin DM;Ravetch JV;Bolland S;Morse HC 3rd;Rickert RC
缺乏PTEN和SHIP磷酸酶的小鼠会自发产生B细胞淋巴瘤。
肌醇磷酸酶——磷酸酶和张力蛋白同源物（PTEN）以及含Src同源2结构域的肌醇磷酸酶（SHIP）对磷脂酰肌醇 - 3 - 激酶（PI3K）介导的造血细胞的生长、存活和增殖起负调控作用。尽管小鼠T细胞中PTEN的缺失会导致致命的T细胞淋巴瘤，但我们发现B细胞中缺乏PTEN或SHIP的动物没有恶性肿瘤的迹象。然而，PTEN和SHIP同时缺失（bPTEN/SHIP - / -）会导致自发且致命的成熟B细胞肿瘤，与边缘区淋巴瘤相符，或者较少见的是滤泡性或中心母细胞性淋巴瘤。bPTEN/SHIP - / - B细胞表现出更强的存活能力，并且表达更多的MCL1和更少的Bim。这些细胞还表达少量的p27kip1和大量的细胞周期蛋白D3，因此似乎随时准备进行增殖性扩张。与正常B细胞不同，bPTEN/SHIP - / - B细胞会因促存活因子B细胞活化因子（BAFF）而增殖。有趣的是，尽管BAFF的可利用性可能促进淋巴瘤进展，但我们证明BAFF对于转移的bPTEN/SHIP - / - B细胞的扩张不是必需的。这项研究表明PTEN和SHIP协同作用以抑制B细胞淋巴瘤，并提供了SHIP是一种肿瘤抑制因子的首个直接证据。因此，对PTEN和SHIP功能的评估对于理解表现出PI3K通路增强激活的人类B细胞恶性肿瘤的病因是相关的。
Mice lacking both PTEN and SHIP phosphatases develop spontaneous B cell lymphoma. The inositol phosphatases phosphatase and tensin homologue (PTEN) and Src homology 2 domain–containing inositol phosphatase (SHIP) negatively regulate phosphatidylinositol-3-kinase (PI3K)–mediated growth, survival, and proliferation of hematopoietic cells. Although deletion of PTEN in mouse T cells results in lethal T cell lymphomas, we find that animals lacking PTEN or SHIP in B cells show no evidence of malignancy. However, concomitant deletion of PTEN and SHIP (bPTEN/SHIP−/−) results in spontaneous and lethal mature B cell neoplasms consistent with marginal zone lymphoma or, less frequently, follicular or centroblastic lymphoma. bPTEN/SHIP−/− B cells exhibit enhanced survival and express more MCL1 and less Bim. These cells also express low amounts of p27kip1 and high amounts of cyclin D3 and thus appear poised to undergo proliferative expansion. Unlike normal B cells, bPTEN/SHIP−/− B cells proliferate to the prosurvival factor B cell activating factor (BAFF). Interestingly, although BAFF availability may promote lymphoma progression, we demonstrate that BAFF is not required for the expansion of transferred bPTEN/SHIP−/− B cells. This study reveals that PTEN and SHIP act cooperatively to suppress B cell lymphoma and provides the first direct evidence that SHIP is a tumor suppressor. As such, assessment of both PTEN and SHIP function are relevant to understanding the etiology of human B cell malignancies that exhibit augmented activation of the PI3K pathway.
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