Global Gene Methylation Profile of CLL Patients and Its Implication in Therapy

Weigang Tong, Guillermo Garcia-Manero

Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX 77030


Chronic lymphocytic leukemia (CLL) is a heterogenous lymphoid malignancy that frequently exhibits genetic alterations such as chromosomal translocations. In addition, epigenetic modifications such as aberrant DNA methylation are also frequently detected in CLL, with consequent silencing of the tumor suppressor genes. The role of these epigenetic changes in facilitating leukemic transformation is unclear. In the current study, we hypothesize that aberrant CpG island methylation in CLL is correlated with inactivation of tumor suppressor genes and this epigenetic alteration plays a key role in the molecular pathogenesis and prognosis of CLL. To test these hypotheses, we propose the following specific aims 1) Genome-wide screening for promoter-associated CpG islands and discover genes that specifically methylated in CLL. 2) Determine the methylation profiles of candidate genes in CLL patients and healthy controls; assess the prognostic significance of aberrant methylation in CLL. 3) Develop clinical trials based on information derived from above aims using hypomethylating agents in individuals with CLL. Our goals are to understand the molecular mechanism of aberrant DNA methylation and their roles in leukemogenesis. Through this study, we want to identify new molecular markers and targets for prognosis, diagnosis and treatment of CLL.