Large granular lymphocyte leukemia: a clonal disorder with autoimmune manifestations

Abstract

Large granular lymphocyte (LGL) leukemia is a rare lymphoproliferative disorder characterized by an expansion of clonal T or natural killer lymphocytes. Neutropenia-related infections and anemia represent the main manifestations. LGL leukemia is frequently associated with autoimmune disorders such as rheumatoid arthritis, Sjögren's syndrome, autoimmune endocrinopathies, vasculitis, or autoimmune cytopenia. Recent advances in the phenotypic and molecular characterization of LGL clones have underscored the pivotal role of a chronic antigenic stimulation and a dysregulation of the Jak/STAT signaling pathway in the pathophysiology linking leukemic-cell expansion and autoimmunity. In more than half of patients, there is a somatic STAT3 mutation. The disease is characterized by an indolent course, but approximately half of all patients will eventually require therapy. The first-line treatment for LGL leukemia is historically based on immunosuppressive agents (methotrexate, cyclophosphamide, or cyclosporine). However, cytokines blocking molecules or Jak/STAT inhibitors represent a new conceptual therapeutic approach for LGL leukemia. In this review, we present an overview of the spectrum of LGL proliferations, potential links between LGL expansion and autoimmunity, and therapeutic approaches.

Graphical abstract

Figure 1.

Workflow for the diagnostic procedure of LGL leukemia. CCL22, C-C motif chemokine ligand 22; KIR, killer- cell immunoglobulin-like receptors.

Figure 2.

Spectrum of LGL expansion ranging from reactive LGL to an aggressive form of LGL leukemia. AIHA, auto-immune hemolytic anemia; ITP, immune thrombocytopenia; T-CUS, T-cell clones of uncertain significance.

Figure 3.

Spectrum of LGL leukemia and associated diseases. AA, aplastic anemia; CLL, chronic lymphocytic leukemia; ITP, immune thrombocytopenia; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; PNH, paroxysmal nocturnal hemoglobinuria; Sjögren Sd, Sjögren syndrome; SLE, systemic lupus erythematosus.

Figure 4.

Links between STAT3 mutation, autoimmune conditions, and LGL expansion. AA, aplastic anemia; GOF, gain-of-function; IPD, inherited photoreceptor degeneration.

Figure 5.

Treatment options for LGL leukemia. AKT, protein kinase B; EPO, erythropoietin; ERK, extracellular signal-regulated kinase; GCSF, granulocyte colony-stimulating factor; HDAC, histone deacetylase; HMA, hypomethylating agents; IL, interleukin; IL-R, interleukin receptor; MEK, mitogen-activated protein kinase kinase; MIB1, Mindbomb E3 ubiquitin protein ligase 1; NFKB, nuclear factor-kappa B; PI3K, phosphoinositide 3-kinase; RANTES, regulated on activation, normal T cell expressed and secreted.