Genomic Complexity and Clinical Outcome in Chronic Lymphocytic Leukemia

描述(申请人提供)：慢性淋巴细胞性白血病是西方世界最常见的白血病。本病的诊断和分期取决于临床和实验室结果。该病的临床病程是高度多变的，治疗和预后变量正在不断改进。识别最具侵袭性的CLL亚型的生物标志物是一个研究重点，因为正是这些患者承担了不成比例的CLL死亡负担。在目前已知的生物标志物中，只有相对罕见的del17p(诊断时占所有CLL病例的5%-7%)识别出诊断后数年内死亡风险较高的患者。因此，识别del17p在CLL疾病管理中具有重要意义，并已导致CLL风险适应治疗方法的发展。与急性髓系白血病不同的是，在CLL中，核型变化在适当的治疗选择中起主导作用，基于遗传损害的治疗和咨询仍在发展和完善。由于CLL细胞在体外不能很好地生长，因此很难全面地研究CLL的基因组变化。因此，一个重大的技术突破是间期荧光原位杂交技术在CLL基因组研究中的应用，它描绘了5个有预后意义的染色体异常：del13q14(约50%)、del11q22-q23(~10%)、三体12(~15-20%)、del17p13(~5-7%)和del6q21。间期FISH现在被用于临床实践中对CLL患者进行风险分层，del17p或del11q的存在已经确定了对标准治疗反应持续时间较短的CLL患者亚群。尽管FISH测试在CLL中很重要，但这项技术有很大的缺点。最突出的警告之一是对基因组的有偏见的评估，因此无法可靠地检测出具有多种染色体异常的CLL(具有复杂核型的CLL)。为了克服CLL基因组分析中的这些困难，我们和其他人使用了SNP阵列来高分辨率地表征CLL基因组。这项分析的一个结果是发现了一组CLL患者(约15%-40%)，他们具有多个亚染色体丢失和获得(高基因组复杂性)，表现出非常快的疾病进展和对标准治疗的不良反应持续时间。在这项建议中，我们希望扩大我们对具有高基因组复杂性的CLL患者的初步观察，以充分探索这一观察的临床意义，并对这一现象的分子机制得出初步的见解。我们预计，通过这些研究，具有高基因组复杂性的CLL患者将被确认为早期需要治疗的高危人群，以及对传统治疗反应差导致过早死亡的高风险人群，从而确定新药开发应针对的相当大的高危CLL患者亚群，并应对其进行改进的咨询。

DESCRIPTION (provided by applicant): CLL is the most common leukemia in the Western world. Diagnosis and staging of the disease is made by clinical and laboratory findings. The clinical course of the disease is highly variable, and treatment and prognostic variables are continuously being refined. Identification of biomarkers that identify the most aggressive CLL subtypes is a research priority as it is these patients that carry a disproportional share of the burden of CLL mortality. Of the currently known biomarkers, only the relatively rare del17p (5%-7% of all CLL cases at diagnosis) identifies patients with high risk for death within years of diagnosis. Identification of del17p is therefore of substantial importance in CLL disease management and has resulted in the development of risk-adapted therapy approaches to CLL. Unlike acute myelogenous leukemia, where karyotypic changes play a dominant role in the appropriate selection of therapy, in CLL, therapy and counseling based on genetic lesions are still being developed and refined. Genomic changes in CLL have been difficult to study comprehensively, as CLL cells do not grow well ex vivo. A major technical breakthrough, therefore, has been the application of interphase fluorescent in situ hybridization to the study of CLL genomes, which delineated five prognostically significant chromosomal aberrations: del13q14 (about 50%), del11q22-q23 (~10%), trisomy 12 (~15-20%), del17p13 (~5-7%) and del6q21. Interphase FISH is now used in clinical practice to risk-stratify CLL patients and presence of del17p or del11q has identified a subgroup of CLL patients with poor response duration to standard therapy. Despite the importance of FISH testing in CLL, this technique has significant shortcomings. One of the most prominent caveats is the biased assessment of the genome and consequently the inability to reliably detect CLL with multiple chromosomal abnormalities (CLL with complex karyotypes). To overcome these difficulties in CLL genome analysis, we and others have employed SNP-arrays to characterize the CLL genome at high resolution. One outcome of this analysis has been the discovery and initial characterization of a subgroup of CLL patients (~15-40%) with multiple sub-chromosomal losses and gains (high genomic complexity) that display very rapid disease progression and poor response duration to standard therapies. In this proposal, we wish to extend our initial observation on CLL patients with high genomic complexity to fully explore the clinical significance of this observation and to derive initial insights into the molecular mechanisms of this phenomenon. We anticipate that through these studies, CLL patients with high genomic complexity will be confirmed to be of high risk for early need of therapy and for poor response to conventional therapy resulting in untimely death, thus identifying a substantial subpopulation of very high risk CLL patients towards which new drug development should be targeted and to which refined counseling should be applied.