Cancer Dis：JAK3基因突变为淋巴瘤潜在治疗靶标

近日Cancer Discovery杂志上刊登的一项研究显示：NK / T细胞淋巴瘤基本都存在JAK3基因突变。JAK3抑制剂可能有助于治疗这些淋巴瘤患者。

新加坡国立癌症中心医学博士Bin Tean Teh说：在我们开始这项工作之前，很少有人知道是什么样的遗传和分子缺陷导致NK / T细胞淋巴瘤，因此也没有有效的治疗手段，这种类型的癌症预后也极差。

为了确定基因突变，研究人员测序了四名NK/T细胞淋巴瘤细胞病人所有基因。除了已知的与癌症相关的基因突变，他们发现一半患者癌细胞存在JAK3基因突变。

突变使NK/T细胞淋巴瘤细胞株生长不依赖于生长因子IL-2，这意味着该突变引起JAK3失调激活，而JAK3可能是一个很好的药物靶标。

目前正在进行三期临床研究评估的一种治疗类风湿疾病的JAK抑制剂，也能诱导细胞凋亡，促使NK/T细胞淋巴瘤细胞株死亡。

Teh说，目前，我们正在把JAK3突变上升到对NK / T细胞淋巴瘤有治疗价值的这个层面上来对待，并且正在测试一些激酶抑制剂。

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.