Genes encoding members of the JAK-STAT pathway or epigenetic regulators are recurrently mutated in T-cell prolymphocytic leukaemia
Genes encoding members of the JAK-STAT pathway or epigenetic regulators are recurrently mutated in T-cell prolymphocytic leukaemia
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DOI：
10.1111/bjh.13952
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发表时间：
2016-04-01
影响因子：
6.5
通讯作者：
Siebert, Reiner
中科院分区：
文献类型：
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作者：
Lopez, Cristina;Bergmann, Anke K.;Siebert, Reiner
T 细胞幼淋巴细胞白血病（T-PLL）是一种侵袭性白血病。 T-PLL 中的主要遗传改变是导致 TRD/TRA-TCL1A 融合的 inv(14)(q11q32)/t(14;14)(q11;q32)，或与 TRD/TRA-MTCP1 融合相关的 t(X;14)(q28;q11)。然而，完整的肿瘤表型的出现需要额外的配合异常。尽管二次染色体畸变的模式非常保守，但变化的目标在很大程度上是未知的。我们分析了 43 个特征明确的 T-PLL 基因 JAK3、STAT5B 和 RHOA 热点突变的队列。此外，我们选择了 23 个 T-PLL 病例的子集，对已知在 T 细胞和其他血液肿瘤中反复突变的 54 个基因进行突变筛查。分别在 30% (13/43) 和 21% (8/39) 的病例中检测到 JAK3 和 STAT5B 基因研究区域的激活突变，并且是相互排斥的。此外，我们在 13% (3/23) 的病例中发现了编码表观遗传调节因子 EZH2 的基因突变，在 17% (4/23) 中发现了编码 TET2 的基因突变，在 9% (2/23) 的病例中发现了编码 BCOR 的基因突变。我们证实 JAK-STAT 通路是一个主要的突变靶点，并鉴定了 T-PLL 中反复突变的表观遗传调节因子。这些发现补充了 T-PLL 中二次畸变的突变谱，并强调了 T-PLL 中表观遗传调节因子的潜在治疗相关性。
T-cell prolymphocytic leukaemia (T-PLL) is an aggressive leukaemia. The primary genetic alteration in T-PLL are the inv(14)(q11q32)/t(14;14)(q11;q32) leading to TRD/TRA-TCL1A fusion, or the t(X;14)(q28;q11) associated with TRD/TRA-MTCP1 fusion. However, additional cooperating abnormalities are necessary for emergence of the full neoplastic phenotype. Though the pattern of secondary chromosomal aberrations is remarkably conserved, targets of the changes are largely unknown. We analysed a cohort of 43 well-characterized T-PLL for hotspot mutations in the genes JAK3, STAT5B and RHOA. Additionally, we selected a subset of 23 T-PLL cases for mutational screening of 54 genes known to be recurrently mutated in T-cell and other haematological neoplasms. Activating mutations in the investigated regions of the JAK3 and STAT5B genes were detected in 30% (13/43) and 21% (8/39) of the cases, respectively, and were mutually exclusive. Further, we identified mutations in the genes encoding the epigenetic regulators EZH2 in 13% (3/23), TET2 in 17% (4/23) and BCOR in 9% (2/23) of the cases. We confirmed that the JAK-STAT pathway is a major mutational target, and identified epigenetic regulators recurrently mutated in T-PLL. These findings complement the mutational spectrum of secondary aberrations in T-PLL and underscore the potential therapeutical relevance of epigenetic regulators in T-PLL.