Cyclic nucleotide phosphodiesterases isoforms as novel biomarkers in CLL

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DESCRIPTION (provided by applicant): Chronic lymphocytic leukemia (CLL), the most common form of adult leukemia, shows a highly variable clinical course spanning from rapidly aggressive to indolent behavior. Patients with aggressive CLL require early treatment while those with indolent CLL generally exhibit a long-lived disease without need of therapy. Currently, clinical staging by the Rai and Binet criteria remains the foundation for determining prognosis and indication for treatment. However, ~50% of patients with early-stage disease, as defined by those criteria, develop more advanced disease and die of CLL or its complications. Importantly, the Rai and Binet staging systems focus on the quantity, rather than on the characteristics, of the leukemic cells. New prognostic indicators, such as the mutational status of the immunoglobulin variable heavy chain region (IgVH), expression of CD38 and ZAP-70 are linked to the molecular characteristics of leukemic cells and have been reported to predict the clinical course and overall survival. IgVH status is a strong independent prognostic factor but IgVH status analysis is laborious, costly and inaccessible for most clinical laboratories. Leukemia-cell expression of CD38 and ZAP-70 was found to correlation with the expression of unmutated IgVH genes to predict a poor prognosis. However, there are no standard, widely used procedures to assess CD 38 and ZAP-70 expression. For routine evaluation of B-CLL patients, a cost- and time-efficient method to obtain optimal prognostic information is thus desirable but does not yet exist. Cyclic nucleotide phosphodiesterases (PDE) catalyze the hydrolysis of cAMP and/or cGMP, thereby controlling their intracellular levels and ability to regulate functions that include cell growth and death. The differential expression of PDE isoforms in diseased cells has the potential to influence cell physiology and identify new drug targets. My preliminary data indicate that CLL cells have a unique profile of expression of PDE isoforms. This unique PDE isoform profile thus relates to the malignant B cells in CLL and may provide a PDE "signature" that could serve as a biomarker for this disease. QPCR (quantitative real-time reverse transcription-PCR) has become a widely used technique for the detection and quantification of RNA targets and is increasingly used in novel clinical diagnostic assay. QPCR methods are relatively simple and rapid, cost-effective, yet sensitive and specific, therefore propose to undertake studies to address the following Specific Aims: 1. The PDE mRNA expression pattern may serve as a prognostic marker to classify patients with indolent and aggressive CLL. 2. The mRNA expression of PDE7B or the ratio of PDE7B mRNA expression vs. that of other PDE isoforms may predict time to initiation of treatment, or response to treatment, in B-CLL patients. Successful completion of these aims will provide a new biomarker in CLL to aid in the diagnosis, prognosis, prediction of time to an response to treatment and possibly suggest new therapeutic approaches for this disease. PUBLIC HEALTH RELEVANCE: Chronic lymphocytic leukemia (CLL), the most common form of adult leukemia, shows a highly variable clinical course spanning from rapidly aggressive, requiring early treatment to indolent behavior, which presents a long- lived disease without need of therapy. Currently, a cost and time efficient method to differentiate between these two forms of CLL does not exist. Based on preliminary studies the proposed research seeks to quantify and establish that cyclic nucleotide phosphodiesterases (PDE) isoforms whose expression is uniquely changed in CLL, may not only provide a biomarker, but also provide the drug target for this disease.