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).

Public Health Relevance

The proposed study has the potential to impact human health by identifying genomic changes associated with LGL leukemia. Currently there are no curative therapies for LGL leukemia and often multiple therapies must be attempted in order to find an effective therapy. Additionally, these studies represent a unique opportunity to identify critical regulatory interactions in normal CD8+ terminal effector memory cells that are normally difficult to study, but have important functions in the control of viral infections and cancer. We strongly believe that the identification of key mutations in LGL will lead to both predictive markers of treatment response and new targets for therapeutic intervention. The assembled multidisciplinary team is uniquely suited to integrate genomic data (Hardison) with network modeling (Albert) that combined with the extensive knowledge of LGL leukemia biology and an extensive patient registry (Loughran) ensures success for work that is proposed.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Howcroft, Thomas K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Virginia
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Olson, Kristine C; Kulling Larkin, Paige M; Signorelli, Rossana et al. (2018) Vitamin D pathway activation selectively deactivates signal transducer and activator of transcription (STAT) proteins and inflammatory cytokine production in natural killer leukemic large granular lymphocytes. Cytokine 111:551-562
Philipsen, Sjaak; Hardison, Ross C (2018) Evolution of hemoglobin loci and their regulatory elements. Blood Cells Mol Dis 70:2-12
Wang, T Tiffany; Yang, Jun; Zhang, Yong et al. (2018) IL-2 and IL-15 blockade by BNZ-1, an inhibitor of selective ?-chain cytokines, decreases leukemic T-cell viability. Leukemia :
Yang, Jun; LeBlanc, Francis R; Dighe, Shubha A et al. (2018) TRAIL mediates and sustains constitutive NF-?B activation in LGL leukemia. Blood 131:2803-2815
Kulling, Paige M; Olson, Kristine C; Hamele, Cait E et al. (2018) Dysregulation of the IFN-?-STAT1 signaling pathway in a cell line model of large granular lymphocyte leukemia. PLoS One 13:e0193429
Savola, Paula; Brück, Oscar; Olson, Thomas et al. (2018) Somatic STAT3 mutations in Felty syndrome: an implication for a common pathogenesis with large granular lymphocyte leukemia. Haematologica 103:304-312
Kulling, Paige M; Olson, Kristine C; Olson, Thomas L et al. (2017) Vitamin D in hematological disorders and malignancies. Eur J Haematol 98:187-197
Olson, Kristine C; Kulling, Paige M; Olson, Thomas L et al. (2017) Vitamin D decreases STAT phosphorylation and inflammatory cytokine output in T-LGL leukemia. Cancer Biol Ther 18:290-303
Zhang, Yu; Hardison, Ross C (2017) Accurate and reproducible functional maps in 127 human cell types via 2D genome segmentation. Nucleic Acids Res 45:9823-9836
Andersson, Emma I; Tanahashi, Takahiro; Sekiguchi, Nodoka et al. (2016) High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia. Blood 128:2465-2468