Aggressive chronic lymphocytic leukemia with elevated genomic complexity is associated with multiple gene defects in the response to DNA double-strand breaks.
Aggressive chronic lymphocytic leukemia with elevated genomic complexity is associated with multiple gene defects in the response to DNA double-strand breaks.
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DOI：
10.1158/1078-0432.ccr-09-2534
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发表时间：
2010-02-01
期刊：
影响因子：
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通讯作者：
Malek SN
中科院分区：
文献类型：
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作者：
Ouillette P;Fossum S;Parkin B;Ding L;Bockenstedt P;Al-Zoubi A;Shedden K;Malek SN
基因组复杂性存在于所有CLL的约15-30%中，并且已经成为CLL中快速疾病进展和短缓解持续时间的强独立预测因子。我们进行这项研究，以促进我们对慢性淋巴细胞白血病基因组复杂性的原因的理解。我们分别从158例和140例患者中获得了放射诱导的细胞凋亡和放射诱导的ATM自磷酸化的定量测量，并采用多变量分析来确定各种生物学变量对CLL基因组复杂性的独立贡献。在这里，我们确定了一个强大的独立的影响，辐射抗性对慢性淋巴细胞白血病的基因组复杂性升高，并描述辐射抗性作为一个预测缩短慢性淋巴细胞白血病的生存。此外，使用多变量分析，我们确定del 17 p/p53畸变，del 11 q，del 13 q14 II型（总是导致Rb丢失）和CD 38表达作为CLL基因组复杂性的独立预测因子，异常p53作为CLL基因组复杂性的预测因子约50%。重点关注del 11 q，我们确定标准化ATM活性是基因组复杂性的适度预测因子，但并不独立于del 11 q。通过基于SNP阵列的del 11 q精细定位，我们发现除了ATM之外，Mre 11和H2 AFX也经常发生单等位基因丢失，这表明DNA-ds-break反应中存在复合del 11 q驻留基因缺陷。我们的定量分析将多种分子缺陷（包括首次del 11 q和13 q14大缺失（II型））与CLL中基因组复杂性升高联系起来，从而表明在基因组不稳定的患者中观察到的CLL临床侵袭性的机制。
Genomic complexity is present in ~15–30% of all CLL and has emerged as a strong independent predictor of rapid disease progression and short remission duration in CLL. We conducted this study to advance our understanding of the causes of genomic complexity in CLL. We have obtained quantitative measurements of radiation-induced apoptosis and radiation-induced ATM auto-phosphorylation in purified CLL cells from 158 and 140 patients, respectively, and have employed multi variate analysis to identify independent contributions of various biological variables on genomic complexity in CLL. Here, we identify a strong independent effect of radiation resistance on elevated genomic complexity in CLL and describe radiation resistance as a predictor for shortened CLL survival. Further, using multivariate analysis, we identify del17p/p53 aberrations, del11q, del13q14 type II (invariably resulting in Rb loss) and CD38 expression as independent predictors of genomic complexity in CLL, with aberrant p53 as a predictor of ~50% of genomic complexity in CLL. Focusing on del11q, we determined that normalized ATM activity was a modest predictor of genomic complexity but was not independent of del11q. Through SNP array-based fine mapping of del11q, we identified frequent mono-allelic loss of Mre11 and H2AFX in addition to ATM, indicative of compound del11q-resident gene defects in the DNA-ds-break response. Our quantitative analysis links multiple molecular defects, including for the first time del11q and large 13q14 deletions (type II), to elevated genomic complexity in CLL, thereby suggesting mechanisms for the observed clinical aggressiveness of CLL in patients with unstable genomes.