Tosello Valeria, Milani Gloria, Martines Annalisa, Macri Nadia, Van Loocke Wouder, Matthijssens Filip, Buldini Barbara, Minuzzo Sonia, Bongiovanni Deborah, Schumacher Richard Fabian, Amadori Alberto, Van Vlierberghe Pieter, Piovan Erich
UOC Immunologia e Diagnostica Molecolare Oncologica, Istituto Oncologico Veneto-IRCCS, Padova 35128, Italy.
Department of Biomolecular Medicine, Ghent University, Ghent 9000, Belgium.
Cells. 2018 Oct 9;7(10):160. doi: 10.3390/cells7100160.
-translocated T-lineage acute lymphoblastic leukemia (T-ALL) is a rare subgroup of T-ALL associated with deletions, inactivation, and absence of or mutations. This subtype of T-ALL has been associated with induction failure and aggressive disease. Identification of drug targets and mechanistic insights for this disease are still limited. Here, we established a human NOTCH1-independent -translocated T-ALL cell line that maintains the genetic and phenotypic characteristics of the parental leukemic clone at diagnosis. The University of Padua T-cell acute lymphoblastic leukemia 13 (UP-ALL13) cell line has all the main features of the above described -translocated T-ALL. Interestingly, UP-ALL13 was found to harbor a heterozygous R882H mutation typically found in myeloid leukemia. Chromatin immunoprecipitation coupled with high-throughput sequencing for histone H3 lysine 27 (H3K27) acetylation revealed numerous putative super-enhancers near key transcription factors, including MYC, MYB, and LEF1. Marked cytotoxicity was found following bromodomain-containing protein 4 (BRD4) inhibition with AZD5153, suggesting a strict dependency of this particular subtype of T-ALL on the activity of super-enhancers. Altogether, this cell line may be a useful model system for dissecting the signaling pathways implicated in NOTCH1-independent T-ALL and for the screening of targeted anti-leukemia agents specific for this T-ALL subgroup.
-易位型T淋巴细胞白血病（T-ALL）是T-ALL的一个罕见亚组，与缺失、失活、缺失或突变相关。这种T-ALL亚型与诱导失败和侵袭性疾病有关。针对这种疾病的药物靶点识别和机制研究仍然有限。在此，我们建立了一种不依赖NOTCH1的易位型T-ALL细胞系，该细胞系在诊断时保持了亲代白血病克隆的遗传和表型特征。帕多瓦大学T细胞急性淋巴细胞白血病13（UP-ALL13）细胞系具有上述易位型T-ALL的所有主要特征。有趣的是，发现UP-ALL13携带一种通常在髓系白血病中发现的杂合R882H突变。染色质免疫沉淀结合组蛋白H3赖氨酸27（H3K27）乙酰化的高通量测序揭示了关键转录因子（包括MYC、MYB和LEF1）附近有许多假定的超级增强子。在用AZD5153抑制含溴结构域蛋白4（BRD4）后发现了明显的细胞毒性，这表明这种特定亚型的T-ALL对超级增强子的活性有严格依赖性。总之，该细胞系可能是一个有用的模型系统，用于剖析与不依赖NOTCH1的T-ALL相关的信号通路，以及筛选针对该T-ALL亚组的靶向抗白血病药物。
