Hematology and Bone Marrow Transplantation Unit, University of Perugia, Perugia, Italy.
Haematologica. 2010 Jan;95(1):79-86. doi: 10.3324/haematol.2009.010413.
Molecular lesions in T-cell acute lymphoblastic leukemias affect regulators of cell cycle, proliferation, differentiation, survival and apoptosis in multi-step pathogenic pathways. Full genetic characterization is needed to identify events concurring in the development of these leukemias.
We designed a combined interphase fluorescence in situ hybridization strategy to study 25 oncogenes/tumor suppressor genes in T-cell acute lymphoblastic leukemias and applied it in 23 adult patients for whom immunophenotyping, karyotyping, molecular studies, and gene expression profiling data were available. The results were confirmed and integrated with those of multiplex-polymerase chain reaction analysis and gene expression profiling in another 129 adults with T-cell acute lymphoblastic leukemias.
The combined hybridization was abnormal in 21/23 patients (91%), and revealed multiple genomic changes in 13 (56%). It found abnormalities known to be associated with T-cell acute lymphoblastic leukemias, i.e. CDKN2A-B/9p21 and GRIK2/6q16 deletions, TCR and TLX3 rearrangements, SIL-TAL1, CALM-AF10, MLL-translocations, del(17)(q12)/NF1 and other cryptic genomic imbalances, i.e. 9q34, 11p, 12p, and 17q11 duplication, del(5)(q35), del(7)(q34), del(9)(q34), del(12)(p13), and del(14)(q11). It revealed new cytogenetic mechanisms for TCRB-driven oncogene activation and C-MYB duplication. In two cases with cryptic del(9)(q34), fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction detected the TAF_INUP214 fusion and gene expression profiling identified a signature characterized by HOXA and NUP214 upregulation and TAF_I, FNBP1, C9orf78, and USP20 down-regulation. Multiplex-polymerase chain reaction analysis and gene expression profiling of 129 further cases found five additional cases of TAF_I-NUP214-positive T-cell acute lymphoblastic leukemia.
Our combined interphase fluorescence in situ hybridization strategy greatly improved the detection of genetic abnormalities in adult T-cell acute lymphoblastic leukemias. It identified new tumor suppressor genes/oncogenes involved in leukemogenesis and highlighted concurrent involvement of genes. The estimated incidence of TAF_I-NUP214, a new recurrent fusion in adult T-cell acute lymphoblastic leukemias, was 4.6% (7/152).
T 细胞急性淋巴细胞白血病中的分子病变影响多步骤发病途径中细胞周期、增殖、分化、存活和凋亡的调节剂。需要进行全面的遗传特征分析，以确定这些白血病发展过程中并发的事件。
我们设计了一种组合的间期荧光原位杂交策略，用于研究 25 个癌基因/肿瘤抑制基因在 T 细胞急性淋巴细胞白血病中的作用，并将其应用于 23 名成人患者，这些患者具有免疫表型、核型分析、分子研究和基因表达谱数据。结果经确认，并与另 129 名 T 细胞急性淋巴细胞白血病成人患者的多重聚合酶链反应分析和基因表达谱结果相整合。
23 名患者中有 21 名（91%）的组合杂交异常，并在 13 名患者（56%）中发现了多个基因组改变。它发现了与 T 细胞急性淋巴细胞白血病相关的已知异常，即 CDKN2A-B/9p21 和 GRIK2/6q16 缺失、TCR 和 TLX3 重排、SIL-TAL1、CALM-AF10、MLL 易位、del(17)(q12)/NF1 和其他隐匿性基因组失衡，即 9q34、11p、12p 和 17q11 重复、del(5)(q35)、del(7)(q34)、del(9)(q34)、del(12)(p13)和 del(14)(q11)。它揭示了 TCRB 驱动的致癌基因激活和 C-MYB 复制的新细胞遗传学机制。在 2 例隐匿性 del(9)(q34)中，荧光原位杂交和逆转录聚合酶链反应检测到 TAF_INUP214 融合，基因表达谱分析确定了一个特征为 HOXA 和 NUP214 上调以及 TAF_I、FNBP1、C9orf78 和 USP20 下调的特征。对 129 例进一步病例的多重聚合酶链反应分析和基因表达谱分析发现，另外 5 例 TAF_I-NUP214 阳性 T 细胞急性淋巴细胞白血病病例。
我们的组合间期荧光原位杂交策略大大提高了成人 T 细胞急性淋巴细胞白血病中遗传异常的检测能力。它确定了新的参与白血病发生的肿瘤抑制基因/癌基因，并强调了基因的并发参与。TAF_I-NUP214 的估计发生率为 4.6%（7/152），这是成人 T 细胞急性淋巴细胞白血病中的一种新的复发性融合。
