? DESCRIPTION (provided by applicant): LGL leukemia results from a clonal expansion of cytotoxic T lymphocytes with a terminal effector memory (TEMRA) phenotype. LGL leukemia patients have multiple clinical phenotypes including chronic neutropenia, pure red cell aplasia, and rheumatoid arthritis. The major focus of this proposal is to identify and understand how genomic changes contribute to the pathogenesis of LGL leukemia as well as normal TEMRA biology. Our collaborative group has recently completed whole genome sequencing of matched LGL clone and normal saliva samples from three patients. An additional 48 genome pairs will be sequenced by the time this proposal would be funded. Preliminary analysis of these three genome pairs indicate an average of 8,000 somatic DNA substitutions as well as evidence of copy number variation and other genome structural changes. Our goal is to understand how these genome changes contribute to the genesis and pathological manifestations of LGL leukemia. In Aim 1, we focus on analyzing the protein coding changes as well as identifying the numerous other genomic changes with less rapidly definable function. In order to gain a more complete understanding of how non-coding genome changes contribute to LGL we will then conduct a series of ENCODE type experiments to identify important genomic regions in LGL (Aim 2). We will then screen our large patient registry to determine the prevalence of these mutations in LGL leukemia and integrate the newly identified interaction data and mutation data into our network model of LGL leukemia survival pathways. In addition, we will correlate mutations with clinical parameters to determine their usefulness in predicting treatment responses to current therapies and individual disease phenotypes (Aim 3).
|Effective start/end date||12/1/15 → 11/30/20|
- National Institutes of Health: $547,547.00
- National Institutes of Health: $609,097.00
- National Institutes of Health: $590,474.00
- National Institutes of Health: $609,457.00
- National Institutes of Health: $630,575.00