Coustan-Smith Elaine, Mullighan Charles G, Onciu Mihaela, Behm Frederick G, Raimondi Susana C, Pei Deqing, Cheng Cheng, Su Xiaoping, Rubnitz Jeffrey E, Basso Giuseppe, Biondi Andrea, Pui Ching-Hon, Downing James R, Campana Dario
Department of Oncology, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
Lancet Oncol. 2009 Feb;10(2):147-56. doi: 10.1016/S1470-2045(08)70314-0. Epub 2009 Jan 13.
About a fifth of children with acute T-lymphoblastic leukaemia (T-ALL) succumb to the disease, suggesting an unrecognised biological heterogeneity that might contribute to drug resistance. We postulated that T-ALL originating from early T-cell precursors (ETPs), a recently defined subset of thymocytes that retain stem-cell-like features, would respond poorly to lymphoid-cell-directed therapy. We studied leukaemic cells, collected at diagnosis, to identify cases with ETP features and determine their clinical outcome.
Leukaemic cells from 239 patients with T-ALL enrolled at St Jude Children's Research Hospital (n=139) and in the Italian national study Associazione Italiana Ematologia Oncologia Pediatrica (AIEOP) ALL-2000 (n=100) were assessed by gene-expression profiling, flow cytometry, and single nucleotide polymorphism array analysis. Probabilities of survival and treatment failure were calculated for subgroups considered to have ETP-ALL or typical T-ALL.
30 patients (12.6%) had leukaemic lymphoblasts with an ETP-related gene-expression signature or its associated distinctive immunophenotype (CD1a(-), CD8(-), CD5(weak) with stem-cell or myeloid markers). Cases of ETP-ALL showed increased genomic instability, in terms of number and size of gene lesions, compared with those with typical T-ALL. Patients with this form of leukaemia had high risk of remission failure or haematological relapse (72% [95% CI 40-100] at 10 years vs 10% [4-16] at 10 years for patients with typical T-ALL treated at St Jude Children's Research Hospital; and 57% [25-89] at 2 years vs 14% [6-22] at 2 years for patients treated in the AIEOP trial).
ETP-ALL is a distinct, previously unrecognised, pathobiological entity that confers a poor prognosis with use of standard intensive chemotherapy. Its early recognition, by use of the gene expression and immunophenotypic criteria outlined here, is essential for the development of an effective clinical management strategy.
US National Cancer Institute, Cariplo Foundation, Citta della Speranza Foundation, Italian Association for Cancer Research (AIRC), Italian Ministry for University and Research, and American Lebanese Syrian Associated Charities (ALSAC).
约五分之一的急性T淋巴细胞白血病（T-ALL）患儿死于该疾病，这表明存在未被认识的生物学异质性，可能导致耐药性。我们推测，起源于早期T细胞前体（ETP）的T-ALL，即最近定义的保留干细胞样特征的胸腺细胞亚群，对淋巴细胞定向治疗反应不佳。我们研究了诊断时收集的白血病细胞，以确定具有ETP特征的病例并确定其临床结局。
对来自圣裘德儿童研究医院登记的239例T-ALL患者（n = 139）以及意大利全国性研究意大利儿科血液肿瘤协会（AIEOP）ALL-2000（n = 100）中的白血病细胞进行基因表达谱分析、流式细胞术和单核苷酸多态性阵列分析。计算被认为患有ETP-ALL或典型T-ALL的亚组的生存和治疗失败概率。
30例患者（12.6%）的白血病原始淋巴细胞具有与ETP相关的基因表达特征或其相关的独特免疫表型（CD1a(-)、CD8(-)、CD5(弱) 伴有干细胞或髓系标志物）。与典型T-ALL患者相比，ETP-ALL病例在基因损伤的数量和大小方面显示出基因组不稳定性增加。患有这种白血病形式的患者缓解失败或血液学复发风险高（圣裘德儿童研究医院治疗的典型T-ALL患者10年时为72% [95% CI 40 - 100]，而10年时为10% [4 - 16]；AIEOP试验中治疗的患者2年时为57% [25 - 89]，而2年时为14% [6 - 22]）。
ETP-ALL是一种独特的、以前未被认识的病理生物学实体，使用标准强化化疗预后不良。通过使用此处概述的基因表达和免疫表型标准对其进行早期识别，对于制定有效的临床管理策略至关重要。
美国国立癌症研究所、卡里普洛基金会、希望之城基金会、意大利癌症研究协会（AIRC）、意大利大学与研究部以及美国黎巴嫩叙利亚联合慈善机构（ALSAC）。
