Genomic and Single-Cell Characterization of Clonal Proliferative Disorders of Large Granular Lymphocytes
Xing, Jeffrey, Biomedical Engineering - School of Engineering and Applied Science, University of Virginia
Loughran, Thomas, MD-INMD Hem/Onc, University of Virginia
Large granular lymphocyte (LGL) leukemia is a chronic blood cancer with persistent, clonal proliferation of cytotoxic lymphocytes. Patients are managed on lifelong immunosuppressive therapy due to lack of a reliable curative strategy and incomplete understanding of disease pathogenesis. Neither leukemia cells nor their rare normal counterpart cells are well characterized, making direct comparisons difficult to contextualize. Moreover, the well-known mutations of STAT3 are absent in a substantial subset of patients, leaving open other etiologies as drivers of disease.
In this work, several measurement modalities are bioinformatically integrated to better understand disease subtypes. First, a genome-wide characterization of the mutational landscape in leukemia is applied which uncovered additional molecular alterations in epigenetic regulators, chemokine signaling, and cell activation pathways, connecting this leukemia to other hematological disorders. Second, the heterogeneous cell types in leukemia are directly compared to currently known healthy counterpart cells using high-dimensional immunophenotyping, which more precisely identified a convergent transcriptional regulatory state involved in disease.
Collectively, these efforts may better define clinical disease subtypes and shed light on the initiation and progression of leukemia clones.
PHD (Doctor of Philosophy)
cytotoxic T-cell NK NKT GD gamma delta, genomics genome exome sequencing WES WGS, VDJ TCR sequencing HLA typing, mass cytometry CyTOF, CITEseq ADTseq, scRNAseq RNAseq
National Cancer Institute (NCI)National Institute of General Medical Sciences (NIGMS)