NATURE:B细胞淋巴癌起源新解

  弥漫性B细胞淋巴瘤是一种常见的恶性肿瘤，关于其起源及原因，历来有很多的说法。但是，最近，加州大学微生物和免疫学学院等人，在《SCIENCE》发表文章，对弥漫性B细胞淋巴瘤的起源及原因进行了研究和分析。
  09年一篇文章曾经介绍过相关内容介绍：他们在作用于老鼠的实验中发现，鞘氨醇-1 - 磷酸受体-2（S1PR2），一种Gα12 和Gα13偶联受体，可以促进生长调节，作用于生发中心（淋巴母细胞中心）B细胞。最近又有对GCB-DLBCL深入测序研究发现了这种肿瘤的几个基因突变，包括GNA13（编码Gα13）和S1PR2。
  而本实验进一步进行了研究。由此本文研究人员们进行了体内体外实验。发现：GCB-DLBCL相关的S1PR2突变往往会打断受体的蛋白激酶B信号转导通路和破坏抑制转移功能。小鼠敲除Gα13的生发中心B细胞、人类GCB-DLBCL细胞都无法抑制应答S1P（鞘氨醇磷酸酯）的蛋白激酶磷酸化和转移，小鼠敲除Gα13的生发中心B细胞会长成B细胞起源的淋巴癌，它不像淋巴细胞，只在淋巴器官中不参与循环。值得一提的是，去除Gα13，而非S1PR2，会使生发中心B细胞进入淋巴液和血液中。GCB-DLBCL细胞常会发生Arhgef1（Gα13效应元件）的突变，缺少Arhgef1也会使生发中心B细胞扩散。
  Gα13-和S1PR2缺失的不完全拟表型使研究人员们发现了P2RY8，一种突变的孤儿受体（未找到内源配体），在GCB-DLBCL和另一种B细胞起源的恶性肿瘤（伯基特淋巴瘤）中发现，P2RY8也会抑制生发中心B细胞的生长和促进Gα13通路的生成。
  这些结果证明依靠Gα13的信号通路对于抑制生发中心B细胞的异常生长、扩散发挥了双重功效，即对于生发中心B细胞起源淋巴癌的发生有抑制作用。
  文章全文参见：
  Germinal centre B-cell-like diffuse large B-cell lymphoma (GCB-DLBCL) is a common malignancy, yet the signalling pathways that are deregulated and the factors leading to its systemic dissemination are poorly defined1, 2. Work in mice showed that sphingosine-1-phosphate receptor-2 (S1PR2), a Gα12 and Gα13 coupled receptor, promotes growth regulation and local confinement of germinal centre B cells3, 4. Recent deep sequencing studies of GCB-DLBCL have revealed mutations in many genes in this cancer, including in GNA13 (encoding Gα13) and S1PR2 (refs 5,6, 7). Here we show, using in vitro and in vivo assays, that GCB-DLBCL-associated mutations occurring in S1PR2 frequently disrupt the receptor’s Akt and migration inhibitory functions. Gα13-deficient mouse germinal centre B cells and human GCB-DLBCL cells were unable to suppress pAkt and migration in response to S1P, and Gα13-deficient mice developed germinal centre B-cell-derived lymphoma. Germinal centre B cells, unlike most lymphocytes, are tightly confined in lymphoid organs and do not recirculate. Remarkably, deficiency in Gα13, but not S1PR2, led to germinal centre B-cell dissemination into lymph and blood. GCB-DLBCL cell lines frequently carried mutations in the Gα13 effector ARHGEF1, and Arhgef1 deficiency also led to germinal centre B-cell dissemination. The incomplete phenocopy of Gα13- and S1PR2 deficiency led us to discover that P2RY8, an orphan receptor that is mutated in GCB-DLBCL and another germinal centre B-cell-derived malignancy, Burkitt’s lymphoma, also represses germinal centre B-cell growth and promotes confinement via Gα13. These findings identify a Gα13-dependent pathway that exerts dual actions in suppressing growth and blocking dissemination of germinal centre B cells that is frequently disrupted in germinal centre B-cell-derived lymphoma.

http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13765.html#/main
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