淋巴瘤是一種屬于免疫系統(tǒng)的實(shí)體性惡性腫瘤,。白血細(xì)胞不斷分裂，并異常地?cái)U(kuò)散至全身,。
淋巴瘤可分為B細(xì)胞淋巴瘤和T細(xì)胞淋巴瘤兩類,。當(dāng)機(jī)體的分子檢測(cè)機(jī)制出現(xiàn)錯(cuò)誤時(shí)B細(xì)胞或T細(xì)胞發(fā)生分裂失控從而導(dǎo)致淋巴瘤。桑福德-伯納姆醫(yī)學(xué)研究所（Sanford-Burnham Medical Research Institute）炎性疾病計(jì)劃的負(fù)責(zé)人Robert Rickert領(lǐng)導(dǎo)的科研小組最近開展了一項(xiàng)新的研究,，檢測(cè)了兩種酶SHIP和PTEN對(duì)于B細(xì)胞生長(zhǎng)和增殖的影響,。研究論文發(fā)表在10月18日的《實(shí)驗(yàn)醫(yī)學(xué)雜志》（Journal of Experimental Medicine）上。研究證實(shí)SHIP和PTEN共同作用抑制B細(xì)胞淋巴瘤,。新發(fā)現(xiàn)為當(dāng)前淋巴瘤的治療方法的開發(fā)指明了新方向,。
“科學(xué)家們圍繞PTEN已開展了非常多的研究，”Rickert博士說：“這是我們第一次證實(shí)SHIP是B細(xì)胞的一個(gè)主要的腫瘤抑制因子,。”
T細(xì)胞可直接殺傷感染細(xì)胞,，而B細(xì)胞則需生成特異性的抗體中和或抵抗外源微生物。機(jī)體需要維持足夠數(shù)量的淋巴細(xì)胞發(fā)揮免疫功能,，但是當(dāng)淋巴細(xì)胞發(fā)生過量增殖時(shí)就可能導(dǎo)致淋巴瘤發(fā)生,。PI3K是一種重要的促進(jìn)細(xì)胞生長(zhǎng)、存活和增殖的酶,。PI3K信號(hào)異?？蓪?dǎo)致各種腫瘤發(fā)生。研究證實(shí)PTEN和SHIP具有抑制PI3K信號(hào)通路的作用,。當(dāng)T細(xì)胞中PTEN缺失時(shí),，細(xì)胞會(huì)發(fā)生生長(zhǎng)失控從而導(dǎo)致T細(xì)胞淋巴瘤。在新研究中研究人員驚訝地發(fā)現(xiàn)當(dāng)B細(xì)胞僅出現(xiàn)PTEN或SHIP缺失時(shí)并不會(huì)影響細(xì)胞,，但是當(dāng)研究人員處理小鼠B細(xì)胞使其同時(shí)喪失PTEN和SHIP時(shí),，小鼠發(fā)生了致命性的B細(xì)胞異常。
研究人員希望了解PTEN和SHIP突變是否確實(shí)會(huì)導(dǎo)致人類發(fā)生淋巴瘤,。在與加州大學(xué)芝加哥分校的Michael David博士的早期合作研究中,，Rickert博士和同事們發(fā)現(xiàn)感染或損傷引起的炎癥會(huì)減少SHIP的表達(dá),。在新研究中研究人員證實(shí)當(dāng)B細(xì)胞僅發(fā)生PTEN突變時(shí)不會(huì)對(duì)細(xì)胞造成損傷，而當(dāng)發(fā)生突變并伴有炎癥時(shí)則有可能導(dǎo)致淋巴瘤發(fā)生,。
Rickert 說：“人們通常認(rèn)為一個(gè)基因與一類癌癥相關(guān),。事實(shí)上癌癥是一種多基因疾病。細(xì)胞從正常向異常轉(zhuǎn)化過程中通常會(huì)發(fā)生多重?fù)p傷,。在本研究中我們構(gòu)建了一個(gè)模型顯示了B細(xì)胞中發(fā)生的事件,。”
“我們的研究不僅有助于深入地了解B細(xì)胞生物學(xué)特性，還可為當(dāng)前的淋巴瘤治療提供指導(dǎo),?？茖W(xué)家們?cè)岢鲆环N治療策略，通過消除機(jī)體內(nèi)的BAFF治療藥物耐受性B細(xì)胞,。利用新的B細(xì)胞淋巴瘤模型,，我們發(fā)現(xiàn)缺失BAFF的B淋巴瘤細(xì)胞仍然可以增殖，”Rickert博士說,。
值得指出的是,，新研究為開發(fā)模擬PTEN和SHIP活性的抗淋巴瘤藥物提供了支持。“多個(gè)公司正在開發(fā)PI3K抑制劑治療某些類型的淋巴瘤,。我們?yōu)镻I3K依賴的B細(xì)胞惡性腫瘤的研究提供了一個(gè)有用的臨床前模型,。（生物谷Bioon.com）
生物谷推薦英文摘要：
JEM doi: 10.1084/jem.20091962
Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases
Ana V. Miletic1, Amy N. Anzelon-Mills1, David M. Mills1, Sidne A. Omori1, Irene M. Pedersen2,3, Dong-Mi Shin4, Jeffrey V. Ravetch6, Silvia Bolland5, Herbert C. Morse III4, and Robert C. Rickert1
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.
