Genomics of LGL leukemia and select other rare leukemia/lymphomas

Moosic, Katharine B.; Paila, Umadevi; Olson, Kristine C.; Dziewulska, Karolina; Wang, T. Tiffany; Xing, Jeffrey C.; Feith, David J.; Olson, Thomas L.

doi:10.1016/j.beha.2019.06.003

Cited by 14 publications

(6 citation statements)

References 92 publications

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“…However, recent publications report mutations in additional regions of the protein, such as the coiled-coil domain, some of which exhibit an activating phenotype. Their inclusion yields an overall STAT3 somatic mutation rate of >50% in LGL leukemia (12)(13)(14).…”

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Intersection Between Large Granular Lymphocyte Leukemia and Rheumatoid Arthritis

et al. 2022

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Large granular lymphocyte (LGL) leukemia, a rare hematologic malignancy, has long been associated with rheumatoid arthritis (RA), and the diseases share numerous common features. This review aims to outline the parallels and comparisons between the diseases as well as discuss the potential mechanisms for the relationship between LGL leukemia and RA. RA alone and in conjunction with LGL leukemia exhibits cytotoxic T-cell (CTL) expansions, HLA-DR4 enrichment, RA-associated autoantibodies, female bias, and unknown antigen specificity of associated T-cell expansions. Three possible mechanistic links between the pathogenesis of LGL leukemia and RA have been proposed, including LGL leukemia a) as a result of longstanding RA, b) as a consequence of RA treatment, or c) as a driver of RA. Several lines of evidence point towards LGL as a driver of RA. CTL involvement in RA pathogenesis is evidenced by citrullination and granzyme B cleavage that modifies the repertoire of self-protein antigens in target cells, particularly neutrophils, killed by the CTLs. Further investigations of the relationship between LGL leukemia and RA are warranted to better understand causal pathways and target antigens in order to improve the mechanistic understanding and to devise targeted therapeutic approaches for both disorders.

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Intersection Between Large Granular Lymphocyte Leukemia and Rheumatoid Arthritis

et al. 2022

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“…Most STAT3 mutations in the SH2 domain create a hydrophobic change in the amino acid. 7,61 The Y640F mutant can homodimerize independently of cytokine stimulation, and thus, carry out transcriptional activities, 62 however, it is likely that in most cases mutants still depend on upstream cytokine stimulation. 63 In the Original Cohort, the five highest data points were all D661 mutations, with four changed to tyrosine (polar side chain with phosphorylation capability) and one changed to isoleucine (hydrophobic side chain) ( Figure 4A).…”

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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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“…The JAK/STAT pathway plays a central role in the pathophysiology of NK-LGL leukemia. Constitutive activation of STAT3 was initially reported in 2001 (16) and an activating mutation of STAT3 was identified in the SH2 domain on two predominant hotspots (D661 and Y640) in LGL leukemia (17), as well as in NK/T and ATLL lymphomas (18). This mutation induces constitutive phosphorylation and STAT3 unit dimerization leading to the transcription of anti-apoptotic genes such as Mcl-1 belonging to the Bcl-2 family.…”

Section: Pathophysiology Of Nk-lgl Leukemiamentioning

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Toward a Better Classification System for NK-LGL Disorders

et al. 2022

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Large granular lymphocytic leukemia is a rare lymphoproliferative disorder characterized by a clonal expansion of T-lineage lymphocyte or natural killer (NK) cells in 85 and 15% of cases respectively. T and NK large granular leukemia share common pathophysiology, clinical and biological presentation. The disease is characterized by cytopenia and a frequent association with autoimmune manifestations. Despite an indolent course allowing a watch and wait attitude in the majority of patients at diagnosis, two third of the patient will eventually need a treatment during the course of the disease. Unlike T lymphocyte, NK cells do not express T cell receptor making the proof of clonality difficult. Indeed, the distinction between clonal and reactive NK-cell expansion observed in several situations such as autoimmune diseases and viral infections is challenging. Advances in our understanding of the pathogenesis with the recent identification of recurrent mutations provide new tools to prove the clonality. In this review, we will discuss the pathophysiology of NK large granular leukemia, the recent advances in the diagnosis and therapeutic strategies.

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Genomics of LGL leukemia and select other rare leukemia/lymphomas

Cited by 14 publications

References 92 publications

Intersection Between Large Granular Lymphocyte Leukemia and Rheumatoid Arthritis

Intersection Between Large Granular Lymphocyte Leukemia and Rheumatoid Arthritis

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

Toward a Better Classification System for NK-LGL Disorders

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