Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome
Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome
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DOI：
10.1182/blood-2009-08-239681
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发表时间：
2010-12-02
期刊：
影响因子：
20.3
通讯作者：
Willman, Cheryl L.
中科院分区：
文献类型：
--
作者：
Harvey, Richard C.;Mullighan, Charles G.;Willman, Cheryl L.
为了解决儿童高危B前体急性淋巴细胞白血病（ALL）中的遗传异质性，这是一个临床上定义的不良风险组，其已知的复发性细胞遗传学异常较少，我们对一组207例接受统一治疗的高危ALL儿童进行了基因表达谱分析。表达谱与全基因组DNA拷贝数异常以及临床和预后特征相关。基因表达谱数据的无监督聚类在这些高危ALL患者中揭示了8个独特的聚类组，其中2个与已知的染色体易位[t(1;19)(TCF3 - PBX1)或MLL]相关，6个缺乏任何先前已知的细胞遗传学病变。一个独特的聚类组的特征是不同的离群基因AGAP1、CCNJ、CHST2/7、CLEC12A/B和PTPRM高表达；ERG DNA缺失；4年无复发生存率为94.7%±5.1%，而队列的4年无复发生存率为63.5%±3.7%（P = 0.01）。第二个聚类组的特征是BMPR1B、CRLF2、GPR110和MUC4高表达；EBF1、IKZF1、RAG1 - 2和IL3RA - CSF2RA频繁缺失；JAK突变和CRLF2重排（P < 0.0001）；以及西班牙裔（P < 0.001），其4年无复发生存率非常低（21.0%±9.5%；P < 0.001）。这些研究揭示了高危ALL中显著的临床和遗传异质性，并指出了可能作为诊断、风险分类和治疗新靶点的新基因。（《血液》2010年；116(23):4874 - 4884）
To resolve the genetic heterogeneity within pediatric high-risk B-precursor acute lymphoblastic leukemia (ALL), a clinically defined poor-risk group with few known recurring cytogenetic abnormalities, we performed gene expression profiling in a cohort of 207 uniformly treated children with high-risk ALL. Expression profiles were correlated with genome-wide DNA copy number abnormalities and clinical and outcome features. Unsupervised clustering of gene expression profiling data revealed 8 unique cluster groups within these high-risk ALL patients, 2 of which were associated with known chromosomal translocations (t(1;19)(TCF3-PBX1) or MLL), and 6 of which lacked any previously known cytogenetic lesion. One unique cluster was characterized by high expression of distinct outlier genes AGAP1, CCNJ, CHST2/7, CLEC12A/B, and PTPRM; ERG DNA deletions; and 4-year relapse-free survival of 94.7% +/- 5.1%, compared with 63.5% +/- 3.7% for the cohort (P = .01). A second cluster, characterized by high expression of BMPR1B, CRLF2, GPR110, and MUC4; frequent deletion of EBF1, IKZF1, RAG1-2, and IL3RA-CSF2RA; JAK mutations and CRLF2 rearrangements (P < .0001); and Hispanic ethnicity (P < .001) had a very poor 4-year relapse-free survival (21.0% +/- 9.5%; P < .001). These studies reveal striking clinical and genetic heterogeneity in high-risk ALL and point to novel genes that may serve as new targets for diagnosis, risk classification, and therapy. (Blood. 2010;116(23):4874-4884)