Recurrent Mutation of JAK3 in T-Cell Prolymphocytic Leukemia
Recurrent Mutation of JAK3 in T-Cell Prolymphocytic Leukemia
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DOI：
10.1002/gcc.22141
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发表时间：
2014-04-01
影响因子：
3.7
通讯作者：
Siebert, Reiner
中科院分区：
文献类型：
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作者：
Bergmann, Anke K.;Schneppenheim, Sina;Siebert, Reiner
T细胞前淋巴细胞白血病(T-PLL)是一种胸腺后侵袭性T细胞恶性肿瘤，其特征是复发的inv(14)(Q11q32)/t(14；14)(q11；q32)或t(X；14)(q28；q11)分别导致TCL1或MTCP1基因激活。然而，这些主要的遗传事件不足以驱动白血病的发生。最近，在其他T细胞恶性肿瘤中也发现了JAK3的激活突变。由于JAK3是T细胞成熟所必需的，我们用逐步筛选的方法分析了32例T-PLL患者JAK3基因的突变热点。我们在32名患者中的11名(34%)中发现了14个突变。在我们的队列中检测到的最常见的突变是M511I(在57%的病例中出现)，以前被描述为其他T细胞恶性肿瘤的活动性变化。三名患者携带JAK3的两个突变。2例同时检测到M511I和R657Q，1例检测到V674F和V678L。在后一种情况下，我们可以证明这些突变位于顺式基因中的同一等位基因上。蛋白质建模和对JAK家族其他成员中存在的突变的同源性分析表明，这些突变可能通过扰乱激活环和N和C叶之间的界面，增加催化环的可及性，从而激活JAK3。此外，在21例缺乏JAK3点突变的患者中，有4例核型异常，涉及携带JAK3基因的染色体带19p13。在T-PLL患者中发现反复激活的JAK3突变，可以使用JAK3抑制剂来治疗这种不利的恶性肿瘤，否则患者的预后非常差。©2014 Wiley期刊，Inc.
T‐cell prolymphocytic leukemia (T‐PLL) is an aggressive post‐thymic T‐cell malignancy characterized by the recurrent inv(14)(q11q32)/t(14;14)(q11;q32) or t(X;14)(q28;q11) leading to activation of either theTCL1orMTCP1gene, respectively. However, these primary genetic events are insufficient to drive leukemogenesis. Recently, activating mutations inJAK3have been identified in other T‐cell malignancies. Since JAK3 is essential for T‐cell maturation, we analyzed a cohort of 32 T‐PLL patients for mutational hot spots in theJAK3gene using a step‐wise screening approach. We identified 14 mutations in 11 of 32 patients (34%). The most frequently detected mutation in our cohort was M511I (seen in 57% of cases) previously described as an activating change in other T‐cell malignancies. Three patients carried two mutations inJAK3. In two patients M511I and R657Q were simultaneously detected and in another patient V674F and V678L. In the latter case we could demonstrate that the mutations were on the same allele in cis. Protein modeling and homology analyses of mutations present in other members of the JAK family suggested that these mutations likely activate JAK3, possibly by disrupting the activation loop and the interface between N and C lobes, increasing the accessibility of the catalytic loop. In addition, four of the 21 patients lacking aJAK3point mutation presented an aberrant karyotype involving the chromosomal band 19p13 harboring theJAK3locus. The finding of recurrent activatingJAK3mutations in patients with T‐PLL could enable the use of JAK3 inhibitors to treat patients with this unfavorable malignancy who otherwise have a very poor prognosis. © 2014 Wiley Periodicals, Inc.