Early Predisposing Genes and Risk Stratification for CLL

CLL 的早期易感基因和风险分层

• 批准号: 7715167
• 负责人: ALBERT DE LA CHAPELLE
• 金额: $ 28.93万
• 依托单位: OHIO STATE UNIVERSITY
• 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 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7715167
• 关键词: Alleles; American; Apoptosis; Apoptotic; B-Lymphocytes; Cancer and Leukemia Group B; Chlorambucil; Chronic; Clinical; Clinical Trials; Clonal Evolution; DAP kinase; DNA; DNA Methylation; Data; Development; Diagnosis; Disease; Disease Progression; Down-Regulation; Early treatment; Enrollment; Event; Experimental Leukemia; Family; Gene Expression; Gene Frequency; Genes; Genetic; Human; Human Characteristics; Immunoglobulins; Inferior; Instruction; Laboratories; Lead; Mediating; Molecular; Molecular Abnormality; Mus; Mutate; Natural History; Newly Diagnosed; Outcome; Patients; Phase III Clinical Trials; Phosphotransferases; Predisposition; Process; Progression-Free Survivals; Progressive Disease; Proteins; Randomized; Regulation; Relative (related person); Reproduction spores; Research; Risk; Sampling; Staging; Stratification; Susceptibility Gene; Symptoms; Therapeutic; Time; Transgenic Mice; Work; adult leukemia; base; cell transformation; chronic leukemia; clinically relevant; clinically significant; fludarabine; high risk; improved; interest; leukemia; mouse model; novel; novel strategies; outcome forecast; prevent; response; rituximab

Chronic lymphocyfic leukemia (CLL) is the most common type of adult leukemia whose clinical outcome is predicted in great part by the IgVn gene mutational status. Patients with IgVn un-mutated status (40% of all pafients at diagnosis) develop progressive disease at a median of 3 years and have inferior overall survival. In contrast, IgVn mutated pafients (60% of all CLL pafients at diagnosis) have a median progression time of 9.2 years, with some patients never requiring therapy. Reasons for adverse outcome in IgVn un-mutated disease include in part a high predisposifion to clonal evolufion. Idenfificafion of initiafion and progression events in IgVn un-mutated patients offers the potential to substantially improve risk stratification and also to idenfify novel targets crucial to initiation and progression for which new therapies can be developed. To identify novel initiating and progression events in CLL, our research groups together have employed two novel strategies. The first combines DNA methylation analysis with genetic studies of familial predisposition. This work demonstrated down-regulafion by DNA methylation of the pro-apoptotic gene DAPK1. This event not only is a general characteristic of human CLL but also is associated with familial predisposifion to developing CLL. We also have used the TCL1 transgenic mouse model of CLL that mimics IgVn un-mutated human CLL to identify addifional molecular events involved in CLL initiafion or progression. Molecular events identified in murine CLL were confirmed to also occur in human CLL. We now propose to expand our findings relative to these initiation and progression events through both a translational laboratory aim, focused on DAPK1 in CLL, and a clinical aim, focused on improving risk stratificafion in IgVn un-mutated CLL as part of a large North American Intergroup Phase III trial. Our specific aims are to determine: 1) the importance of DAPK-mediated apoptosis in B-cells, frequency of allele-specific expression in CLL, and mechanisms by which DAPK1 gene expression is regulated in B- cells, with particular focus on regulators potentially relevant to B-cell transformation to CLL; and 2) the significance of baseline and serial molecular events in CLL inifiafion or progression on progression-free survival and clonal evolution in newly diagnosed CLL patients with IgVn un-mutated disease. Our overall hypothesis in this proposal is that improved understanding of inifiafing and progression events in CLL will lead to more effecfive risk stratified approaches for IgVn un-mutated CLL, and also novel targets for which therapies can be developed to potentially prevent clonal evolution or progression of this disease. RELEVANCE (See instructions): This SPORE translational project performs detailed study of the CLL inifiating gene DAPK1 and assesses the impact of select molecular events on treatment free survival and clonal evolution in newly diagnosed IgVn un-mutated pafients. These findings may improve risk of progression of IgVn un-mutated CLL patients and also idenfify novel targets for targeted therapies to prevent clonal evolution or progression of this disease.

慢性淋巴细胞白血病（CLL）是成人白血病中最常见的一种类型，其临床结局是