Genomic Complexity and Clinical Outcome in Chronic Lymphocytic Leukemia

慢性淋巴细胞白血病的基因组复杂性和临床结果

• 批准号: 8053248
• 负责人: Sami Nimer Malek
• 金额: $ 30.86万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053248
• 关键词: Acute Myelocytic Leukemia; Aftercare; Allogenic; Anatomy; Apoptotic; Biological; Biological Factors; Biological Markers; Blood; Bone Marrow Transplantation; Cells; Cessation of life; Chromosomal Gain; Chromosomal Loss; Chromosome abnormality; Chronic Lymphocytic Leukemia; Clinical; Clinical Course of Disease; Complex; Counseling; Cytotoxic Chemotherapy; DNA Double Strand Break; DNA Repair; DNA Sequence Analysis; Data; Data Analyses; Defect; Development; Diagnosis; Disease; Disease Management; Disease Progression; Enrollment; Fluorescent in Situ Hybridization; Foundations; Gene Mutation; Genes; Genetic; Genome; Genomic Instability; Genomics; Health; Individual; Interphase; Investigational Therapies; Karyotype determination procedure; Laboratories; Laboratory Finding; Lesion; Malignant Neoplasms; Maps; Marrow; Measurement; Measures; Molecular; Multivariate Analysis; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Play; Prognostic Factor; Prognostic Marker; Progressive Disease; Recurrence; Reporting; Research Priority; Resolution; Risk; Role; Sampling; Staging; Subgroup; Surrogate Markers; Techniques; Technology; Testing; Time; Trisomy 12; Variant; Western World; base; chemotherapy; clinical practice; clinically significant; cohort; conventional therapy; density; drug development; ds-DNA; functional status; gene therapy; high risk; insight; leukemia; mortality; new technology; novel; prognostic; repaired; response

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.

描述（由申请人提供）：CLL 是西方世界最常见的白血病。该疾病的诊断和分期是根据临床和实验室检查结果进行的。该疾病的临床病程变化很大，治疗和预后变量也在不断完善。识别最具侵袭性的 CLL 亚型的生物标志物是研究的重点，因为这些患者承担着不成比例的 CLL 死亡率负担。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%）可识别诊断后数年内死亡风险较高的患者。因此，del17p 的鉴定对于 CLL 疾病管理非常重要，并导致了针对 CLL 的风险适应治疗方法的开发。与急性髓性白血病不同，核型变化在适当的治疗选择中起主导作用，而在 CLL 中，基于遗传病变的治疗和咨询仍在开发和完善中。由于 CLL 细胞在体外生长不佳，因此很难全面研究 CLL 的基因组变化。因此，一项重大技术突破是将间期荧光原位杂交应用于 CLL 基因组研究，它描绘了五种具有预后意义的染色体畸变：del13q14（约 50%）、del11q22-q23（约 10%）、12 三体(~15-20%)、del17p13 (~5-7%) 和 del6q21。目前，间期 FISH 在临床实践中用于对 CLL 患者进行风险分层，del17p 或 del11q 的存在已确定了对标准治疗反应持续时间较差的 CLL 患者亚组。尽管 FISH 检测在 CLL 中很重要，但该技术有明显的缺点。最突出的警告之一是对基因组的评估有偏差，因此无法可靠地检测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，我们和其他人采用 SNP 阵列以高分辨率表征 CLL 基因组。该分析的一个结果是发现并初步表征了 CLL 患者亚组（约 15-40%），其具有多个亚染色体丢失和增益（基因组复杂性高），显示出疾病进展非常快，且对标准的反应持续时间很差疗法。在本提案中，我们希望将我们的初步观察扩展到具有高基因组复杂性的 CLL 患者，以充分探索这一观察的临床意义，并初步了解这种现象的分子机制。我们预计，通过这些研究，基因组复杂性高的 CLL 患者将被确认为早期需要治疗且对常规治疗反应不佳导致过早死亡的高风险患者，从而确定极高风险 CLL 患者的大量亚群哪些新药开发要针对哪些，哪些要进行精细化辅导。