Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies
Integrated genomic analysis of relapsed childhood acute lymphoblastic leukemia reveals therapeutic strategies
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DOI：
10.1182/blood-2011-04-345595
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发表时间：
2011-11-10
期刊：
影响因子：
20.3
通讯作者：
Carroll, William L.
中科院分区：
文献类型：
--
作者：
Hogan, Laura E.;Meyer, Julia A.;Carroll, William L.
尽管急性淋巴细胞白血病（ALL）儿童的生存率有所提高，但复发后的结局很差。为了了解导致复发和化疗耐药性的遗传事件并确定新的治疗靶点，使用3种高通量测定法来确定复发时的遗传和表观遗传变化。使用复发前体B细胞ALL患儿的诊断/复发骨髓样本，我们评估了基因表达、拷贝数异常（CNAs）和DNA甲基化。基因表达分析揭示了从诊断到复发的差异表达基因的特征，其对于早期（< 36个月）和晚期（>= 36个月）复发是不同的。CNA分析发现了在诊断和复发时共享的CNA，以及在复发时获得的新病变。DNA甲基化分析发现复发时启动子甲基化增加。从诊断到复发，有许多基因改变，在某些情况下，这些基因以前与化疗耐药性有关。整合所有3个平台的结果，鉴定出潜在感兴趣的基因，包括CDKN 2A、COL 6A 2、PTPRO和CSMD 1。虽然我们的研究结果表明，多样性的遗传变化被视为在复发，整合基因表达，CNA和甲基化数据表明可能的收敛WNT和丝裂原活化蛋白激酶途径。（血。2011;118（19）：5218-5226）
Despite an increase in survival for children with acute lymphoblastic leukemia (ALL), the outcome after relapse is poor. To understand the genetic events that contribute to relapse and chemoresistance and identify novel targets of therapy, 3 high-throughput assays were used to identify genetic and epigenetic changes at relapse. Using matched diagnosis/relapse bone marrow samples from children with relapsed B-precursor ALL, we evaluated gene expression, copy number abnormalities (CNAs), and DNA methylation. Gene expression analysis revealed a signature of differentially expressed genes from diagnosis to relapse that is different for early (< 36 months) and late (>= 36 months) relapse. CNA analysis discovered CNAs that were shared at diagnosis and relapse and others that were new lesions acquired at relapse. DNA methylation analysis found increased promoter methylation at relapse. There were many genetic alterations that evolved from diagnosis to relapse, and in some cases these genes had previously been associated with chemoresistance. Integration of the results from all 3 platforms identified genes of potential interest, including CDKN2A, COL6A2, PTPRO, and CSMD1. Although our results indicate that a diversity of genetic changes are seen at relapse, integration of gene expression, CNA, and methylation data suggest a possible convergence on the WNT and mitogen-activated protein kinase pathways. (Blood. 2011;118(19):5218-5226)