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.
Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world and has a highly variable clinical course. Identification of biomarkers that predict the clinical outcome of patients remains a research priority. Our studies aim at defining the role of CLL genomic changes in outcome prognostication in CLL through use of novel technologies able to measure these changes in an unbiased fashion.
|Pasqualucci, Laura; Khiabanian, Hossein; Fangazio, Marco et al. (2014) Genetics of follicular lymphoma transformation. Cell Rep 6:130-40|
|Malek, S N (2013) The biology and clinical significance of acquired genomic copy number aberrations and recurrent gene mutations in chronic lymphocytic leukemia. Oncogene 32:2805-17|
|Ouillette, Peter; Saiya-Cork, Kamlai; Seymour, Erlene et al. (2013) Clonal evolution, genomic drivers, and effects of therapy in chronic lymphocytic leukemia. Clin Cancer Res 19:2893-904|
|Shedden, K; Li, Y; Ouillette, P et al. (2012) Characteristics of chronic lymphocytic leukemia with somatically acquired mutations in NOTCH1 exon 34. Leukemia 26:1108-10|
|Saiya-Cork, Kamlai; Collins, Roxane; Parkin, Brian et al. (2011) A pathobiological role of the insulin receptor in chronic lymphocytic leukemia. Clin Cancer Res 17:2679-92|
|Ouillette, Peter; Collins, Roxane; Shakhan, Sajid et al. (2011) Acquired genomic copy number aberrations and survival in chronic lymphocytic leukemia. Blood 118:3051-61|
|Zhang, X; Reis, M; Khoriaty, R et al. (2011) Sequence analysis of 515 kinase genes in chronic lymphocytic leukemia. Leukemia 25:1908-10|
|Badr, Hoda; Paxton, Raheem J; Ater, Joann L et al. (2011) Health behaviors and weight status of childhood cancer survivors and their parents: similarities and opportunities for joint interventions. J Am Diet Assoc 111:1917-23|
|Ouillette, Peter; Collins, Roxane; Shakhan, Sajid et al. (2011) The prognostic significance of various 13q14 deletions in chronic lymphocytic leukemia. Clin Cancer Res 17:6778-90|
|Parkin, Brian; Ouillette, Peter; Wang, Yin et al. (2010) NF1 inactivation in adult acute myelogenous leukemia. Clin Cancer Res 16:4135-47|
Showing the most recent 10 out of 13 publications