Abstract
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.
Highlights
Large granular lymphocytic (LGL) leukemia is a rare disease that accounts for 2 to 5% of chronic lymphoproliferative disorders [1]
LGL leukemia is mainly characterized by cytopenia, primarily neutropenia predisposing to infections and is frequently associated with an array of autoimmune diseases, in particular rheumatoid arthritis
Diagnosis of LGL leukemia is based on two mandatory criteria which help to Update in natural killer (NK)-LGL Disorders differentiate it from reactive LGL lymphocytosis: cytological identification of lymphocytes with granules > 0.5 G/L observed at least over 6 months and proof of clonality
Summary
Large granular lymphocytic (LGL) leukemia is a rare disease that accounts for 2 to 5% of chronic lymphoproliferative disorders [1]. A TET2 loss-of-function mutation is found in 34% of NK-LGLs. The gene encoding the chemokine CCL22 is mutated in 20% of NK-LGLs. Fas, First Apoptosis Signal; FasL, FasLigand; IL, interleukin; IL-R, interleukin-receptor; Jak, Janus Kinase; STAT3, Signal transducer and activator of transcription 3; PDGF-BB, platelet-derived growth factor BB; MEK, mitogen activated protein kinase; ERK, extracellular-signal-regulated kinase; PI3K, phosphatidyl Inositol 3-Kinase; mTOR, mammalian target of rapamycin; NFkB, nuclear factor kappa B; Mcl, Myeloid cell leukemia; Bcl, B-cell lymphoma 2; CCL22, C-C Motif Chemokine Ligand 22; 5mc, 5-methylcytosin; 5hmc, 5-hydroxymethylcytosin; TET2, Ten-eleven-translocation 2. PDGF-b (Platelet-derived growth factor subunit Beta) produced in excess by clonal LGLs, forms an anti-apoptotic autocrine loop, activating the signaling pathways mentioned above, PI3K-AKT, RAS/MEK1/ERK, and JAK/STAT. Neutropenia is less frequently observed in the NK subtype (29% in T LGL leukemia, as compared to 61% in NK LGL leukemia) [29, 40]
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