Liem Natalia L M, Papa Rachael A, Milross Christopher G, Schmid Michael A, Tajbakhsh Mayamin, Choi Seoyeon, Ramirez Carole D, Rice Alison M, Haber Michelle, Norris Murray D, MacKenzie Karen L, Lock Richard B
Children's Cancer Institute Australia for Medical Research, Sydney, Australia.
Blood. 2004 May 15;103(10):3905-14. doi: 10.1182/blood-2003-08-2911. Epub 2004 Feb 5.
Continuous xenografts from 10 children with acute lymphoblastic leukemia (ALL) were established in nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. Relative to primary engrafted cells, negligible changes in growth rates and immunophenotype were observed at second and third passage. Analysis of clonal antigen receptor gene rearrangements in 2 xenografts from patients at diagnosis showed that the pattern of clonal variation observed following tertiary transplantation in mice exactly reflected that in bone marrow samples at the time of clinical relapse. Patients experienced diverse treatment outcomes, including 5 who died of disease (median, 13 months; range, 11-76 months, from date of diagnosis), and 5 who remain alive (median, 103 months; range, 56-131 months, following diagnosis). When stratified according to patient outcome, the in vivo sensitivity of xenografts to vincristine and dexamethasone, but not methotrexate, differed significantly (P =.028, P =.029, and P =.56, respectively). The in vitro sensitivity of xenografts to dexamethasone, but not vincristine, correlated significantly with in vivo responses and patient outcome. This study shows, for the first time, that the biologic and genetic characteristics, and patterns of chemosensitivity, of childhood ALL xenografts accurately reflect the clinical disease. As such, they provide powerful experimental models to prioritize new therapeutic strategies for future clinical trials.
在非肥胖糖尿病/重症联合免疫缺陷（NOD/SCID）小鼠中建立了10例急性淋巴细胞白血病（ALL）患儿的连续异种移植模型。相对于原代移植细胞，在传代至第二代和第三代时，观察到生长速率和免疫表型的变化可忽略不计。对2例诊断时患者的异种移植进行克隆抗原受体基因重排分析，结果显示在小鼠中进行三次移植后观察到的克隆变异模式与临床复发时骨髓样本中的模式完全一致。患者的治疗结果各不相同，包括5例死于疾病（从诊断日期起，中位时间为13个月；范围为11 - 76个月），以及5例仍存活（诊断后，中位时间为103个月；范围为56 - 131个月）。根据患者结局进行分层时，异种移植对长春新碱和地塞米松的体内敏感性存在显著差异（分别为P = 0.028、P = 0.029和P = 0.56），但对甲氨蝶呤的敏感性无显著差异。异种移植对地塞米松的体外敏感性（而非对长春新碱的敏感性）与体内反应及患者结局显著相关。本研究首次表明，儿童ALL异种移植的生物学和遗传学特征以及化学敏感性模式准确反映了临床疾病。因此，它们为确定未来临床试验的新治疗策略提供了强大的实验模型。
