Good syndrome presenting with CD8+ T-Cell large granular lymphocyte leukemia

Caperton, Caroline V.; Agrawal, Sudhanshu; Gupta, Sudhir

doi:10.18632/oncotarget.5369

Cited by 14 publications

(8 citation statements)

References 35 publications

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“…T-LGLL clonotypes are known to overexpress cytotoxic and T cell activation-associated genes in comparison with their healthy reactive counterparts 44 , 45 . Here, we also found exhaustion-associated genes, such as LAG3 and TIGIT , among the most upregulated genes between T-LGLL and hyperexpanded cells in healthy controls, but not the previously found PDCD1 ( PD1 ) and HAVCR2 ( TIM-3 ) 44 , 45 . Our in vitro validation suggested that TCR ligation fails to trigger normal degranulation and cytokine production in the T-LGLL clonotypes.…”

Section: Discussionmentioning

confidence: 99%

Single-cell characterization of leukemic and non-leukemic immune repertoires in CD8+ T-cell large granular lymphocytic leukemia

et al. 2022

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T cell large granular lymphocytic leukemia (T-LGLL) is a rare lymphoproliferative disorder of mature, clonally expanded T cells, where somatic-activating STAT3 mutations are common. Although T-LGLL has been described as a chronic T cell response to an antigen, the function of the non-leukemic immune system in this response is largely uncharacterized. Here, by utilizing single-cell RNA and T cell receptor profiling (scRNA+TCRαβ-seq), we show that irrespective of STAT3 mutation status, T-LGLL clonotypes are more cytotoxic and exhausted than healthy reactive clonotypes. In addition, T-LGLL clonotypes show more active cell communication than reactive clones with non-leukemic immune cells via costimulatory cell–cell interactions, monocyte-secreted proinflammatory cytokines, and T-LGLL-clone-secreted IFNγ. Besides the leukemic repertoire, the non-leukemic T cell repertoire in T-LGLL is also more mature, cytotoxic, and clonally restricted than in other cancers and autoimmune disorders. Finally, 72% of the leukemic T-LGLL clonotypes share T cell receptor similarities with their non-leukemic repertoire, linking the leukemic and non-leukemic repertoires together via possible common target antigens. Our results provide a rationale to prioritize therapies that target the entire immune repertoire and not only the T-LGLL clonotype.

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Section: Discussionmentioning

confidence: 99%

Single-cell characterization of leukemic and non-leukemic immune repertoires in CD8+ T-cell large granular lymphocytic leukemia

et al. 2022

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“…T-LGL cells express pan-T-antigens, programmed cell death 1 (PD-1), some NK-cell associated molecules, cytotoxic granules (containing perforin and granzymes) and lack the CD28 co-stimulatory receptor. Detection of CD45RA and further markers of T-cell differentiation suggest a terminally differentiated effector memory (T EM-RA ) phenotype (128,(186)(187)(188). T EM-RA cells are featured by the absence of CCR7, and accordingly, most T-LGL cases in these studies did not show tumor cell expression of CCR7.…”

Section: T-cell Large Granular Lymphocytic Leukemia (T-lgl)mentioning

confidence: 76%

CCR7 in Blood Cancers – Review of Its Pathophysiological Roles and the Potential as a Therapeutic Target

Cuesta-Mateos

Terrón²,

Herling³

2021

Front. Oncol.

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According to the classical paradigm, CCR7 is a homing chemokine receptor that grants normal lymphocytes access to secondary lymphoid tissues such as lymph nodes or spleen. As such, in most lymphoproliferative disorders, CCR7 expression correlates with nodal or spleen involvement. Nonetheless, recent evidence suggests that CCR7 is more than a facilitator of lymphatic spread of tumor cells. Here, we review published data to catalogue CCR7 expression across blood cancers and appraise which classical and novel roles are attributed to this receptor in the pathogenesis of specific hematologic neoplasms. We outline why novel therapeutic strategies targeting CCR7 might provide clinical benefits to patients with CCR7-positive hematopoietic tumors.

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“…The occurrence of low Hgb and high MCV has been reported in two case studies of T-LGL leukemia and an associated disease, but not in the context of STAT3 mutation status. 64,65 A previous study found that STAT3 SH2 domain mutation is correlated with smaller granular lymphocytes in T-LGL leukemia. 66 In particular, a small subset of four patients with unusually small mean lymphocyte diameter all had D661Y mutation (one was Y640F/D661Y) with anemia (two of them were diagnosed with PRCA).…”

Section: Discussionmentioning

confidence: 98%

Large granular lymphocyte leukemia serum and corresponding hematological parameters reveal unique cytokine and sphingolipid biomarkers and associations with STAT3 mutations

et al. 2020

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Large granular lymphocyte (LGL) leukemia is a rare hematological disorder with expansion of the T‐cell or natural killer (NK) cell lineage. Signal transducer and activator of transcription 3 (STAT3) exhibits somatic activating mutations in 30%‐40% of LGL leukemia cases. Transcriptional targets of STAT3 include inflammatory cytokines, thus previous studies have measured cytokine levels of LGL leukemia patients compared to normal donors. Sphingolipid metabolism is a growing area of cancer research, with efforts focused on drug discovery. To date, no studies have examined serum sphingolipids in LGL leukemia patients, and only one study compared a subset of cytokines between the T‐LGL and NK‐LGL subtypes. Therefore, here, we included both LGL leukemia subtypes with the goals of (a) measuring serum sphingolipids for the first time, (b) measuring cytokines to find distinctions between the subtypes, and (c) establishing relationships with STAT3 mutations and clinical data. The serum analyses identified cytokines (EGF, IP‐10, G‐CSF) and sphingolipids (SMC22, SMC24, SMC20, LysoSM) significantly different in the LGL leukemia group compared to normal donors. In a mixed STAT3 mutation group, D661Y samples exhibited the highest mean corpuscular volume (MCV) values. We explored this further by expanding the cohort to include larger groups of single STAT3 mutations. Male D661Y STAT3 samples had lower Hgb and higher MCV compared to wild type (WT) or Y640F counterparts. This is the first report examining large groups of individual STAT3 mutations. Overall, our results revealed novel serum biomarkers and evidence that D661Y mutation may show different clinical manifestation compared to WT or Y640F STAT3.

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Good syndrome presenting with CD8+ T-Cell large granular lymphocyte leukemia

Cited by 14 publications

References 35 publications

Single-cell characterization of leukemic and non-leukemic immune repertoires in CD8+ T-cell large granular lymphocytic leukemia

Single-cell characterization of leukemic and non-leukemic immune repertoires in CD8+ T-cell large granular lymphocytic leukemia

CCR7 in Blood Cancers – Review of Its Pathophysiological Roles and the Potential as a Therapeutic Target

Large granular lymphocyte leukemia serum and corresponding hematological parameters reveal unique cytokine and sphingolipid biomarkers and associations with STAT3 mutations

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