Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia.
Deletion of IKZF1 and prognosis in acute lymphoblastic leukemia.
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DOI：
10.1056/nejmoa0808253
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发表时间：
2009-01-29
期刊：
影响因子：
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通讯作者：
Children's Oncology Group
中科院分区：
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作者：
Mullighan CG;Su X;Zhang J;Radtke I;Phillips LA;Miller CB;Ma J;Liu W;Cheng C;Schulman BA;Harvey RC;Chen IM;Clifford RJ;Carroll WL;Reaman G;Bowman WP;Devidas M;Gerhard DS;Yang W;Relling MV;Shurtleff SA;Campana D;Borowitz MJ;Pui CH;Smith M;Hunger SP;Willman CL;Downing JR;Children's Oncology Group
尽管目前最好的治疗，高达20%的儿科急性淋巴细胞白血病（ALL）患者复发。最近的全基因组分析已经确定了ALL中DNA拷贝数异常的高频率，但这些异常的预后含义尚未明确。我们研究了221名高危b细胞祖性ALL患儿队列，使用单核苷酸多态性微阵列、转录谱分析和诊断时获得的样本重测序。已知高危ALL亚型（即bcr - abl1阳性ALL、次二倍体ALL和婴儿ALL）的儿童被排除在该队列之外。拷贝数异常被确定为不良预后的预测因子，然后在258例b细胞祖性ALL患者的独立验证队列中进行了测试。发现了50多个重复的拷贝数异常，最常见的涉及编码b细胞发育调节因子的基因（原始队列中66.8%的患者）；31.7%的患者参与PAX5, 28.6%的患者参与IKZF1。使用拷贝数异常，我们确定了一个不良预后的预测因子，并在独立验证队列中得到了验证。这一预测因子与IKZF1的改变密切相关，IKZF1是一种编码淋巴转录因子IKAROS的基因。结果不佳患者组的基因表达特征显示造血干细胞基因表达增加，b细胞谱系基因表达减少，与另一种IKZF1缺失频率高的ALL高危亚型bcr - abl1阳性ALL的特征相似。IKZF1的遗传改变与b细胞祖细胞ALL的预后非常差有关。
Despite best current therapy, up to 20% of pediatric patients with acute lymphoblastic leukemia (ALL) have a relapse. Recent genomewide analyses have identified a high frequency of DNA copy-number abnormalities in ALL, but the prognostic implications of these abnormalities have not been defined. We studied a cohort of 221 children with high-risk B-cell–progenitor ALL with the use of single-nucleotide–polymorphism microarrays, transcriptional profiling, and resequencing of samples obtained at diagnosis. Children with known very-high-risk ALL subtypes (i.e., BCR-ABL1–positive ALL, hypodiploid ALL, and ALL in infants) were excluded from this cohort. A copy-number abnormality was identified as a predictor of poor outcome, and it was then tested in an independent validation cohort of 258 patients with B-cell–progenitor ALL. More than 50 recurring copy-number abnormalities were identified, most commonly involving genes that encode regulators of B-cell development (in 66.8% of patients in the original cohort); PAX5 was involved in 31.7% and IKZF1 in 28.6% of patients. Using copy-number abnormalities, we identified a predictor of poor outcome that was validated in the independent validation cohort. This predictor was strongly associated with alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS. The gene-expression signature of the group of patients with a poor outcome revealed increased expression of hematopoietic stem-cell genes and reduced expression of B-cell–lineage genes, and it was similar to the signature of BCR-ABL1–positive ALL, another high-risk subtype of ALL with a high frequency of IKZF1 deletion. Genetic alteration of IKZF1 is associated with a very poor outcome in B-cell–progenitor ALL.