近日Cancer Discovery雜志上刊登的一項(xiàng)研究顯示：NK / T細(xì)胞淋巴瘤基本都存在JAK3基因突變,。JAK3抑制劑可能有助于治療這些淋巴瘤患者,。
新加坡國(guó)立癌癥中心醫(yī)學(xué)博士Bin Tean Teh說(shuō)：在我們開(kāi)始這項(xiàng)工作之前,，很少有人知道是什么樣的遺傳和分子缺陷導(dǎo)致NK / T細(xì)胞淋巴瘤,，因此也沒(méi)有有效的治療手段,，這種類型的癌癥預(yù)后也極差,。
為了確定基因突變,，研究人員測(cè)序了四名NK/T細(xì)胞淋巴瘤細(xì)胞病人所有基因,。除了已知的與癌癥相關(guān)的基因突變,，他們發(fā)現(xiàn)一半患者癌細(xì)胞存在JAK3基因突變。
突變使NK/T細(xì)胞淋巴瘤細(xì)胞株生長(zhǎng)不依賴于生長(zhǎng)因子IL-2,，這意味著該突變引起JAK3失調(diào)激活,，而JAK3可能是一個(gè)很好的藥物靶標(biāo)。
目前正在進(jìn)行三期臨床研究評(píng)估的一種治療類風(fēng)濕疾病的JAK抑制劑,，也能誘導(dǎo)細(xì)胞凋亡,，促使NK/T細(xì)胞淋巴瘤細(xì)胞株死亡。
Teh說(shuō),，目前,，我們正在把JAK3突變上升到對(duì)NK / T細(xì)胞淋巴瘤有治療價(jià)值的這個(gè)層面上來(lái)對(duì)待，并且正在測(cè)試一些激酶抑制劑,。
doi:10.1158/2159-8290.CD-12-0028
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Janus Kinase 3–Activating Mutations Identified in Natural Killer/T-cell Lymphoma
Ghee Chong Koo, Soo Yong Tan, Tiffany Tang, Song Ling Poon, George E. Allen, Leonard Tan, et al.
The molecular pathogenesis of natural killer/T-cell lymphoma (NKTCL) is not well understood. We conducted whole-exome sequencing and identified Janus kinase 3(JAK3) somatic–activating mutations (A572V and A573V) in 2 of 4 patients with NKTCLs. Further validation of the prevalence of JAK3mutations was determined by Sanger sequencing and high-resolution melt (HRM) analysis in an additional 61 cases. In total, 23 of 65 (35.4%) cases harbored JAK3mutations. Functional characterization of the JAK3mutations support its involvement in cytokine-independent JAK/STAT constitutive activation leading to increased cell growth. Moreover, treatment of both JAK3-mutant and wild-type NKTCL cell lines with a novel pan-JAK inhibitor, CP-690550, resulted in dose-dependent reduction of phosphorylated STAT5, reduced cell viability, and increased apoptosis. Hence, targeting the deregulated JAK/STAT pathway could be a promising therapy for patients with NKTCLs.
