López Cristina, Bergmann Anke K, Paul Ulrike, Murga Penas Eva M, Nagel Inga, Betts Matthew J, Johansson Patricia, Ritgen Matthias, Baumann Tycho, Aymerich Marta, Jayne Sandrine, Russell Robert B, Campo Elias, Dyer Martin J S, Dürig Jan, Siebert Reiner
Institute for Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig Holstein, Kiel, Germany.
Department of Paediatrics, Christian-Albrechts-University Kiel & University Hospital Schleswig Holstein, Kiel, Germany.
Br J Haematol. 2016 Apr;173(2):265-73. doi: 10.1111/bjh.13952. Epub 2016 Feb 25.
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.
T细胞原淋巴细胞白血病（T-PLL）是一种侵袭性白血病。T-PLL的主要基因改变是inv(14)(q11q32)/t(14;14)(q11;q32)，导致TRD/TRA-TCL1A融合，或t(X;14)(q28;q11)，与TRD/TRA-MTCP1融合相关。然而，完整肿瘤表型的出现还需要其他协同异常。尽管继发性染色体畸变模式显著保守，但这些变化的靶点大多未知。我们分析了一组43例特征明确的T-PLL，以检测JAK3、STAT5B和RHOA基因中的热点突变。此外，我们选择了23例T-PLL病例的子集，对已知在T细胞和其他血液系统肿瘤中反复突变的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，且二者相互排斥。此外，我们在13%（3/23）的病例中鉴定出编码表观遗传调节因子EZH2的基因突变，在17%（4/23）的病例中鉴定出TET2基因突变，在9%（2/23）的病例中鉴定出BCOR基因突变。我们证实JAK-STAT通路是主要的突变靶点，并鉴定出在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继发性畸变的突变谱，并强调了表观遗传调节因子在T-PLL中的潜在治疗相关性。
