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Large granular lymphocyte (LGL) leukemia results from clonal expansion of CD31 cytotoxic T lymphocytes or CD32 natural killer (NK) cells. Chronic antigen stimulation is postulated to promote long-term survival of LGL leukemia cells through constitutive activation of multiple survival pathways, resulting in global dysregulation of apoptosis and resistance to activation-induced cell death. We reported previously that nuclear factor kB (NF-kB) is a central regulator of the survival network for leukemic LGL. However, the mechanisms that trigger constitutive activation of NF-kB in LGL leukemia remain undefined. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to induce apoptosis in tumor cells but can also activate NF-kB through interaction with TRAIL receptors 1, 2, and 4 (also known as DR4, DR5, and DcR2, respectively). The role of TRAIL has not been studied in LGL leukemia. In this study, we hypothesized that TRAIL interaction with DcR2 contributes to NF-kB activation in LGL leukemia. We observed upregulated TRAIL messenger RNA and protein expression in LGL leukemia cells with elevated levels of soluble TRAIL protein in LGL leukemia patient sera. We also found that DcR2 is the predominant TRAIL receptor in LGL leukemia cells. We demonstrated that TRAIL-induced activation of DcR2 led to increased NF-kB activation in leukemic LGL. Conversely, interruption of TRAIL-DcR2 signaling led to decreased NF-kB activation. Finally, a potential therapeutic application of proteasome inhibitors (bortezomib and ixazomib), which are known to inhibit NF-kB, was identified through their ability to decrease proliferation and increase apoptosis in LGL leukemia cell lines and primary patient cells. [ABSTRACT FROM AUTHOR]

Large granular lymphocytic (LGL) leukemia is characterized by clonal expansion of cytotoxic T cells or natural killer cells. Recently, somatic mutations in the signal transducer and activator of transcription 3 (STAT3) gene were discove!ed in 28% to 40% of LGL leukemia patients. By exome and transcriptome sequencing of 2 STAT3 mutation-negative LGL leukemia patients, we identified a recurrent, somatic missense mutation (V665F) in the Src-like homology 2 domain of the STAT5b gene. Targeted amplicon sequencing of 211 LGL leukemia patients revealed 2 additional patients with STAT5b mutations (N642H), resulting in a total frequency of 2% (4 of 211) of STAT5b mutations across all patients. The Y665F and N642H mutant constructs increased the transcriptional activity of STAT5 and tyrosine (Y694) phosphorylation, which was also observed in patient samples. The clinical course of the disease in patients with the N642H mutation was aggressive and fatal, clearly different from typical LGL leukemia with a relatively favorable outcome. This is the first time somatic STAT5 mutations are discovered in human cancer and further emphasizes the role of STAT family genes in the pathogenesis of LGL leukemia. [ABSTRACT FROM AUTHOR]

T-cell large granular lymphocyte leukemia (T-LGLL) Is characterized by chronic lymphoproliferatlon of cytotoxic T lymphocytes (CTLs) and is associated with lineage-restricted cytopenias. irilroduction of T-cell receptor (TCR) variable β-chain (Vβ) monoclonal antibodies has facilitated identification and enumeration of clonal CTLs by flow cytometry. A highly skewed TCR V(t repertoire identified by flow cytometry is strongly associated With monoclonal CDR3 regions by quantitative sequencing and positive TCR-y rearrangement assays. Therefore, V13 expansions can serve as surrogate markers of CTL clonality to assess clonal kinetics In T-LGLL. We analyzed the TCR repertoire in 143 patients, 71 of which were available for serial measurements over 6 to 96 months. Although the majority (38/71, 54%) maintained a consistent monocional expansion, many (26/71, 37%) unexpectedly displayed a change In the dominant clone, whereby the original CTL clone contracted arid another emerged as demonstrated by V13 typing. Our results demonstrate that the 1-cell repertoire is more dynamic In T-LGLL than recognized previously, Illustrating the heterogeneity of disorders under this categorization. [ABSTRACT FROM AUTHOR]