Cytometric profiling of leukemic cells from large granular lymphocyte leukemia reveals activated precursor cells

Large granular lymphocytic (LGL) leukemia is a rare hematological cancer characterized by a clonal expansion of either cytotoxic T cells or natural killer (NK) cells. These cells normally function to remove cancer cells and virally infected cells. However in LGLL, these cells are expanded even in the absence of known antigens. This abnormal excess of leukemic cells leads to neutropenia, anemia, and fatigue in patients. To investigate the differential abundance of cell types and differential expression of markers between disease subtypes, cytometry data was analyzed from 25 patients and controls (healthy, T-LGLL, and NK-LGLL). As expected, TEMRA cytotoxic T cell type was found to be expanded across T-LGLL samples. Intriguingly, these cells were divided into 2 subpopulations based on CD57+/- expression. Moreover, leukemic cells from patients with known STAT3 mutations exhibited increased expression of CD38, suggesting overactivation. NK-LGLL samples also demonstrated an increase in CD57+ expression relative to normal patients. The chronic NK-LGLL samples displayed an expanded population of NK cells with marker profiles similar to normal samples. However, in aggressive NK-LGLL, an abnormal NK cell type expressing NKT-like markers as well as increased phospho-STAT markers was identified. This abnormal cell type with NKT-like markers suggests a reversion to a less differentiated state while the increase in phospho-STAT markers suggests an increased activation of cellular pathways. Further characterization of these identified leukemic subpopulations and the proteins indicative of their functions may contribute to understanding the pathogenesis and origins of leukemic precursor cells, with the potential to eradicate the disease source.