Differential gene expression patterns and interaction networks in BCR-ABL-positive and -negative adult acute lymphoblastic leukemias
Differential gene expression patterns and interaction networks in BCR-ABL-positive and -negative adult acute lymphoblastic leukemias
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DOI：
10.1200/jco.2006.09.3534
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发表时间：
2007-04-10
影响因子：
45.3
通讯作者：
Sikic, Branimir I.
中科院分区：
文献类型：
--
作者：
Juric, Dejan;Lacayo, Norman J.;Sikic, Branimir I.
目的研究成人急性淋巴细胞白血病（ALL）患者BCR-ABL状态和临床预后的相关基因表达模式和相互作用网络。患者和方法应用DNA微阵列分析来自医学研究理事会UKALL XII/东部肿瘤协作组E2993试验的54例成人ALL标本（21例p185（BCR-ABL）阳性，16例p210（BCR-ABL）阳性和17例BCR-ABL阴性标本）。并在128例成人ALL标本的独立队列中评估其有效性。这组271个差异表达基因（包括GAB 1、CIITA、XBP 1、CD 83、SERPINB 9、PTP 4A 3、NOV、LOX、CTNND 1、BAALC和RAB 21）富集了参与细胞死亡、细胞生长和增殖以及血液系统发育和功能的基因。网络分析表明，这些基因的复杂的相互作用模式，并确定FYN和IL 15的得分最高的网络的枢纽。在BCR-ABL阳性亚组中，我们鉴定了相对于p210（BCR-ABL）阳性ALL，p185（BCR-ABL）阳性ALL中过表达（PILRB、STS-1、SPRY 1）或低表达（TSPAN 16、ADAMTSL 4）的基因。最后，我们构建了一个基于基因表达和相互作用的结果预测因子，由27个基因组成（包括GRB 2、GAB 1、GLI 1、IRS 1、RUNX 2和SPP 1）与BCR-ABL阳性成人ALL的总生存期相关（P = 0.0001），与年龄无关（P =.25）和就诊时WBC计数结论我们发现了BCR-ABL阳性成人ALL的突出分子特征，这可能有助于开发新的治疗靶点和预后标志物。
PurposeTo identify gene expression patterns and interaction networks related to BCR-ABL status and clinical outcome in adults with acute lymphoblastic leukemia ( ALL).Patients and MethodsDNA microarrays were used to profile a set of 54 adult ALL specimens from the Medical Research Council UKALL XII/Eastern Cooperative Oncology Group E2993 trial ( 21 p185(BCR-ABL)-positive, 16 p210(BCR-ABL)-positive and 17 BCR- ABL - negative specimens).ResultsUsing supervised and unsupervised analysis tools, we detected significant transcriptomic changes in BCR- ABL - positive versus - negative specimens, and assessed their validity in an independent cohort of 128 adult ALL specimens. This set of 271 differentially expressed genes ( including GAB1, CIITA, XBP1, CD83, SERPINB9, PTP4A3, NOV, LOX, CTNND1, BAALC, and RAB21) is enriched for genes involved in cell death, cellular growth and proliferation, and hematologic system development and function. Network analysis demonstrated complex interaction patterns of these genes, and identified FYN and IL15 as the hubs of the top-scoring network. Within the BCR- ABL - positive subgroups, we identified genes overexpressed (PILRB, STS-1, SPRY1) or underexpressed (TSPAN16, ADAMTSL4) in p185(BCR-ABL) - positive ALL relative to p210(BCR-ABL) positive ALL. Finally, we constructed a gene expression- and interaction-based outcome predictor consisting of 27 genes ( including GRB2, GAB1, GLI1, IRS1, RUNX2, and SPP1), which correlated with overall survival in BCR- ABL - positive adult ALL ( P =.0001), independent of age ( P =.25) and WBC count at presentation ( P =.003).ConclusionWe identified prominent molecular features of BCR- ABL - positive adult ALL, which may be useful for developing novel therapeutic targets and prognostic markers in this disease.