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: 8450207
• 负责人: Sami Nimer Malek
• 金额: $ 29.12万
• 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/8450207
• 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 Expression Profiling; 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; genome analysis; 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。疾病的诊断和分期是通过临床和实验室检查结果进行的。该疾病的临床过程是高度可变的，治疗和预后变量正在不断完善。识别最具侵袭性的CLL亚型的生物标志物的鉴定是研究的优先事项，因为正是这些患者承担了不成比例的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del 17 p（诊断时所有CLL病例的5%-7%）可识别诊断后数年内死亡风险高的患者。因此，del 17 p的鉴定在CLL疾病管理中具有实质性的重要性，并且已经导致CLL的风险适应性治疗方法的发展。与核型变化在适当选择治疗中起主导作用的急性髓性白血病不同，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细胞离体生长不佳，因此很难全面研究CLL的基因组变化。因此，一项重大的技术突破是间期荧光原位杂交技术应用于CLL基因组的研究，该技术描绘了五种在临床上显著的染色体畸变：del 13 q14（约50%）、del 11 q22-q23（约10%）、12三体（约15-20%）、del 17 p13（约5-7%）和del 6 q21。间期FISH现在用于临床实践中对CLL患者进行风险分层，del 17 p或del 11 q的存在已经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中的重要性，但这种技术具有显著的缺点。最突出的警告之一是对基因组的偏倚评估，因此无法可靠地检测具有多个染色体异常的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，我们和其他人已经采用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一个CLL患者亚组（约15-40%），该亚组具有多个亚染色体丢失和获得（高基因组复杂性），显示出非常快速的疾病进展和对标准疗法的不良反应持续时间。在这项提案中，我们希望扩展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，并获得对这一现象的分子机制的初步见解。我们预计，通过这些研究，具有高基因组复杂性的CLL患者将被证实具有早期治疗需求和对常规治疗反应不良导致过早死亡的高风险，从而确定了大量极高风险CLL患者亚群，应针对其进行新药开发，并应对其进行精细咨询。

项目成果

A pathobiological role of the insulin receptor in chronic lymphocytic leukemia.

• DOI: 10.1158/1078-0432.ccr-10-2058
• 发表时间: 2011-05-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Saiya-Cork K;Collins R;Parkin B;Ouillette P;Kuizon E;Kujawski L;Erba H;Campagnaro E;Shedden K;Kaminski M;Malek SN
• 通讯作者: Malek SN

A Quantitative Analysis of Subclonal and Clonal Gene Mutations before and after Therapy in Chronic Lymphocytic Leukemia.

• DOI: 10.1158/1078-0432.ccr-15-3103
• 发表时间: 2016-09-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Amin NA;Seymour E;Saiya-Cork K;Parkin B;Shedden K;Malek SN
• 通讯作者: Malek SN

The biology and clinical significance of acquired genomic copy number aberrations and recurrent gene mutations in chronic lymphocytic leukemia.

• DOI: 10.1038/onc.2012.411
• 发表时间: 2013-06-06
• 期刊: ONCOGENE
• 影响因子: 8
• 作者: Malek, S. N.

NF1 inactivation in adult acute myelogenous leukemia.

• DOI: 10.1158/1078-0432.ccr-09-2639
• 发表时间: 2010-08-15
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Parkin B;Ouillette P;Wang Y;Liu Y;Wright W;Roulston D;Purkayastha A;Dressel A;Karp J;Bockenstedt P;Al-Zoubi A;Talpaz M;Kujawski L;Liu Y;Shedden K;Shakhan S;Li C;Erba H;Malek SN
• 通讯作者: Malek SN

Clonal evolution, genomic drivers, and effects of therapy in chronic lymphocytic leukemia.

• DOI: 10.1158/1078-0432.ccr-13-0138
• 发表时间: 2013-06-01
• 期刊: Clinical cancer research : an official journal of the American Association for Cancer Research
• 作者: Ouillette P;Saiya-Cork K;Seymour E;Li C;Shedden K;Malek SN
• 通讯作者: Malek SN