(From left) Thomas P. Loughran Jr., MD, and Aakrosh Ratan, PhD
Thomas P. Loughran Jr., MD, director of the UVA Comprehensive Cancer Center, and Aakrosh Ratan, PhD, associate professor in the Department of Genome Sciences, have been awarded a five-year, $3.4 million National Cancer Institute grant to study the genomic architecture of large granular lymphocyte leukemia (LGLL).
LGLL is a hematological malignancy that results from a clonal expansion of antigen-driven cytotoxic lymphocytes and is associated with inflammatory cytokine production, autoimmune disease, and cytopenia. There are no curative therapies for LGLL, and the immunosuppressive agents prescribed to reduce symptoms exhibit slow and incomplete responses.
Dr. Loughran first identified LGLL while working as a fellow at the Fred Hutchinson Cancer Research Center and it has been a focus of his research group since then. This translational research is enabled and strengthened by the resources of the LGL Leukemia Registry, which is housed in the Loughran Lab and is the only national registry that collects, manages and analyzes information on people with LGLL. Over 2,000 patients have consented to join the registry and provide biological samples and clinical records that support research studies such as this funded grant.
Leveraging the registry, the Drs. Loughran and Ratan have identified recurrent somatic variants and changes in gene expression, chromatin accessibility, and DNA methylation to define the molecular pathogenesis of LGLL in some of the largest patient cohorts sequenced to date. These efforts identified several LGLL-relevant genes and pathways associated with specific clinical phenotypes and subtypes. The studies were published in Blood, and one of them is summarized in a UVA Health press release here.
This newly funded study will define the consequences of these identified molecular alterations and their impact on LGLL biology and function using preclinical models and patient cohorts. The project will leverage high-throughput experimental methods and computational techniques to identify and characterize cell-type-specific functional changes in LGLL of high translational relevance, leading to the identification of predictive markers of treatment response and new targets for therapeutic intervention.
David Feith, PhD, John Luckey, MD, PhD, Chongzhi Zang, PhD, and Todd Fox, PhD, are collaborators on the award. The LGL Leukemia Registry is supported by the Bess Family Charitable Fund and a gift from a generous anonymous donor. The Loughran Lab research program is additionally supported by P01CA171983, R01AR079404, and a Scarlet Feather Fund donation to UVA’s Translational Orphan Blood Cancer Research Initiative.
Filed Under: Research