Toward Defining the Functional Methylome in Acute Lymphoblastic Leukemia

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DESCRIPTION (provided by applicant): To date, investigations of DNA methylation in candidate genes or using low-resolution genome-wide technologies have provided an incomplete view of the aberrant methylation present in various tumor types. The immediate goal of the proposal is to narrow this knowledge gap and to elucidate the mechanism(s) that are responsible for the aberrant disease-specific targeting of loci methylated in acute lymphoblastic leukemia (ALL). We propose to pursue three aims: 1) Generate high-resolution, genome-wide methylation profiles in normal and malignant precursor B-cells from controls and individuals with childhood ALL using a genome-wide methylation microarray; 2) Elucidate sequence specific and region-specific targets of aberrant methylation by comparing CGI methylation patterns among neoplastic and normal bone marrows; and 3) Generate CpG site-specific CGI methylation maps to determine the relationships between location and extent of methylation and gene expression using a massively parallel sequencing technology and qRT-PCR. This work will progress the deciphering of the ALL methylome and its contribution to the ALL phenotype and the developed analytical strategy should define an excellent template for studying aberrant methylation in other tumor types. The proposed investigations will provide the foundation for the candidate's long-term career goal to become an independent researcher and faculty member at a Tier I research institution where, the long-term objectives: 1) Researching the relationships between genetics and epigenetics; and 2) Investigating the consequences of in utero exposures on the establishment of epigenetic events will be pursued. The training plan includes advanced analytical, cancer pathobiology, scientific writing and technical training. Also included are career development activities such as networking, opportunities to present scientific data, one-on-one mentoring and training in the responsible conduct of research. The training will be under the tutelage of Dr. M. Sharon Stack and Dr. Charles Caldwell at the University of Missouri-School of Medicine. Dr. Stack will assist the candidate in the transition to independence by aiding in the candidate's integration into the scientific community both at the local and national levels. Dr. Caldwell will assist the candidate in the transition to independence by releasing all data to the candidate, facilitating new collaborations, and committing the finances, facilities, equipment and technical support required to complete the training. RELEVANCE: Elucidation of the effects of epigenetic alterations on the silencing of tumor-suppressor genes will provide fundamental knowledge regarding the causes of cancer. This will allow for the identification of potential target sequences that can be used as diagnostic or prognostic markers. This is of the utmost importance because it could lead to novel treatments to restore gene function using DNA methylation inhibitors.