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Large granular lymphocyte leukaemias (LGL) are rare lymphoproliferative syndromes characterised by clonal expansion of T or NK lymphocytes in 85 and 15% of cases respectively. Interestingly, T and NK LGL leukaemias share a common pathophysiology and similar clinical and biological presentations. This lymphoproliferative syndrome is characterised by cytopenias and a frequent association with autoimmune diseases or manifestations. It is an indolent disease that in most cases allows for an abstinence-only strategy at diagnosis. However, the majority of patients will require initiation of treatment during follow-up. As NK cells lack a TCR, obtaining evidence of clonality in NK-ALL leukaemias is difficult. This is crucial in view of possible reactive expansions in the context of viral infections or dysimmune diseases. The diagnostic approach has been facilitated by the progress made in recent years in the understanding of the pathophysiology and the recent identification of recurrent mutations. In this review, we will discuss the pathophysiology of NK LGL leukaemias, present recent advances in diagnostic strategies before discussing therapeutic management. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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.

Distinguishing chronic lymphoproliferative disorders of NK cells (CLPD-NK) from reactive NK-cell expansion is challenging. We assessed the value of killer immunoglobulin-like receptor(KIR) phenotyping and targeted high-throughput sequencing in a cohort of 114 consecutive patients with NK cell proliferation, retrospectively assigned to a CLPD-NK group (n = 46) and a reactive NK group (n = 68). We then developed an NK-cell clonality score combining flow cytometry and molecular profiling with a positive predictive value of 93%. STAT3 and TET2 mutations were respectively identified in 27% and 34% of the patients with CLPD-NK, constituting a new diagnostic hallmark for this disease. TET2-mutated CLPD-NK preferentially exhibited a CD16low phenotype, more frequently displayed a lower platelet count, and was associated with other hematologic malignancies such as myelodysplasia. To explore the mutational clonal hierarchy of CLPD-NK, we performed whole-exome sequencing of sorted, myeloid, T, and NK cells and found that TET2 mutations were shared by myeloid and NK cells in 3 of 4 cases. Thus, we hypothesized that TET2 alterations occur in early hematopoietic progenitors which could explain a potential link between CLPD-NK and myeloid malignancies. Finally, we analyzed the transcriptome by RNA sequencing of 7 CLPD-NK and evidenced 2 groups of patients. The first group displayed STAT3 mutations or SOCS3 methylation and overexpressed STAT3 target genes. The second group, including 2 TET2-mutated cases, significantly underexpressed genes known to be downregulated in angioimmunoblastic T-cell lymphoma. Our results provide new insights into the pathogenesis of NK-cell proliferative disorders and, potentially, new therapeutic opportunities., (© 2021 by The American Society of Hematology.)