Department of Oncological Sciences, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.
Oncogene. 2011 Oct 13;30(41):4289-96. doi: 10.1038/onc.2011.138. Epub 2011 May 9.
T-cell acute lymphoblastic leukemia (T-ALL) is a challenging clinical entity with high rates of induction failure and relapse. To discover the genetic changes occurring in T-ALL, and those contributing to relapse, we studied zebrafish (Danio rerio) T-ALL samples using array comparative genomic hybridization (aCGH). We performed aCGH on 17 T-ALLs from four zebrafish T-ALL models, and evaluated similarities between fish and humans by comparing all D. rerio genes with copy number aberrations (CNAs) with a cohort of 75 published human T-ALLs analyzed by aCGH. Within all D. rerio CNAs, we identified 893 genes with human homologues and found significant overlap (67%) with the human CNA dataset. In addition, when we restricted our analysis to primary T-ALLs (14 zebrafish and 61 human samples), 10 genes were recurrently altered in > 3 zebrafish cancers and ≥ 4 human cases, suggesting a conserved role for these loci in T-ALL transformation across species. We also conducted iterative allo-transplantation with three zebrafish malignancies. This technique selects for aggressive disease, resulting in shorter survival times in successive transplant rounds and modeling refractory and relapsed human T-ALL. Fifty-five percent of original CNAs were preserved after serial transplantation, demonstrating clonality between each primary and passaged leukemia. Cancers acquired an average of 34 new CNAs during passaging. Genes in these loci may underlie the enhanced malignant behavior of these neoplasias. We also compared genes from CNAs of passaged zebrafish malignancies with aCGH results from 50 human T-ALL patients who failed induction, relapsed or would eventually relapse. Again, many genes (88/164) were shared by both datasets. Further, nine recurrently altered genes in passaged D. rerio T-ALL were also found in multiple human T-ALL cases. These results suggest that zebrafish and human T-ALLs are similar at the genomic level, and are governed by factors that have persisted throughout evolution.
T 细胞急性淋巴细胞白血病（T-ALL）是一种具有高诱导失败率和复发率的极具挑战性的临床实体。为了发现 T-ALL 中发生的遗传变化以及导致复发的遗传变化，我们使用 array 比较基因组杂交（aCGH）研究了斑马鱼（Danio rerio）T-ALL 样本。我们对来自四个斑马鱼 T-ALL 模型的 17 个 T-ALL 进行了 aCGH 分析，并通过将所有 D. rerio 基因与拷贝数异常（CNAs）与通过 aCGH 分析的 75 个人类 T-ALL 队列进行比较，评估了鱼类和人类之间的相似性。在所有 D. rerio 的 CNAs 中，我们鉴定了 893 个具有人类同源物的基因，并发现与人类 CNA 数据集有显著重叠（67%）。此外，当我们将分析限制在原发性 T-ALL（14 个斑马鱼和 61 个人类样本）时，有 10 个基因在>3 个斑马鱼癌症和≥4 个人类病例中反复改变，表明这些基因座在跨物种 T-ALL 转化中具有保守作用。我们还对三种斑马鱼恶性肿瘤进行了迭代同种异体移植。该技术选择侵袭性疾病，导致连续移植轮次的存活时间缩短，并模拟难治性和复发性人类 T-ALL。在连续移植后，55%的原始 CNA 得以保留，表明每个原发性和传代白血病之间存在克隆性。癌症在传代过程中获得了平均 34 个新的 CNA。这些基因座中的基因可能是这些肿瘤恶性行为增强的基础。我们还将传代斑马鱼恶性肿瘤的 CNA 中的基因与 50 名诱导失败、复发或最终复发的人类 T-ALL 患者的 aCGH 结果进行了比较。同样，两个数据集有许多基因（88/164）共享。此外，在传代 D. rerio T-ALL 中反复改变的九个基因也在多个人类 T-ALL 病例中发现。这些结果表明，斑马鱼和人类 T-ALL 在基因组水平上相似，并且受进化过程中一直存在的因素控制。
