LGL leukemia: from pathogenesis to treatment

Abstract

Large granular lymphocyte (LGL) leukemia has been recognized by the World Health Organization classifications amongst mature T-cell and natural killer (NK) cell neoplasms. There are 3 categories: chronic T-cell leukemia and NK-cell lymphocytosis, which are similarly indolent diseases characterized by cytopenias and autoimmune conditions as opposed to aggressive NK-cell LGL leukemia. Clonal LGL expansion arise from chronic antigenic stimulation, which promotes dysregulation of apoptosis, mainly due to constitutive activation of survival pathways including Jak/Stat, MapK, phosphatidylinositol 3-kinase–Akt, Ras–Raf-1, MEK1/extracellular signal-regulated kinase, sphingolipid, and nuclear factor-κB. Socs3 downregulation may also contribute to Stat3 activation. Interleukin 15 plays a key role in activation of leukemic LGL. Several somatic mutations including Stat3, Stat5b, and tumor necrosis factor alpha-induced protein 3 have been demonstrated recently in LGL leukemia. Because these mutations are present in less than half of the patients, they cannot completely explain LGL leukemogenesis. A better mechanistic understanding of leukemic LGL survival will allow future consideration of a more targeted therapeutic approach than the current practice of immunosuppressive therapy.

Vitamin D pathway activation selectively deactivates signal transducer and activator of transcription (STAT) proteins and inflammatory cytokine production in natural killer leukemic large granular lymphocytes

“…Patients with the more common subtype of this cancer exhibit an expansion of primarily CD3+CD8+CD57+ T cells (~85%), while individuals with the less common subtype exhibit an expansion of primarily CD3-CD16+CD56+ NK cells (~10%) [1]. An aggressive form of NK-LGLL is seen in <5% of LGL disorders, typically in Asia, and is associated with Epstein-Barr virus [2, 3].…”

“…An aggressive form of NK-LGLL is seen in <5% of LGL disorders, typically in Asia, and is associated with Epstein-Barr virus [2, 3]. Diagnosis of LGLL is established by increased lymphocyte count and confirmation of the expanded T cell or NK cell population by flow cytometry [1, 2]. T-LGLL clonality can be established by the T cell receptor (TCR) rearrangement test; however, NK cells do not express TCR, so skewed killer-cell immunoglobin-like receptors can suggest but not establish clonality [1, 2].…”

“…Diagnosis of LGLL is established by increased lymphocyte count and confirmation of the expanded T cell or NK cell population by flow cytometry [1, 2]. T-LGLL clonality can be established by the T cell receptor (TCR) rearrangement test; however, NK cells do not express TCR, so skewed killer-cell immunoglobin-like receptors can suggest but not establish clonality [1, 2]. The chronic form of LGLL can be managed by a watch-and-wait approach, or treated with immunosuppressant therapies for symptomatic neutropenia or anemia [2].…”

Donor derived T-cell large granular lymphocyte leukemia after cord blood transplant for pediatric T-cell lymphoblastic leukemia

“…LGL leukemia most commonly affects the elderly with a median age of 60, although cases in younger adults and very rarely pediatric patients have been reported (1–4). In most cases T-LGL leukemia is associated with an indolent clinical course characterized by cytopenias and autoimmune phenomena, with infections due to neutropenia being among the most common presenting symptoms (4–7). LGL leukemia mortality is mainly due to severe infections,although this occurs in <10% of patients and the overall survival at 10 years is approximately 70% (8,9).…”

Large granular lymphocyte cells and immune dysregulation diseases – the chicken or the egg?

“…13,14 The presumed common pathogenesis of LGL leukemia and immune dysregulations such as FS, CD, and bone marrow failure and related conditions (AA, hypoplastic MDS, PNH) would pave the way for more sophisticated treatment strategies than the current general immune suppressive modalities which are frequently applied. 15 Such targeted strategies would have to exploit common molecular aberrations, one of the most promising approaches being STAT3 inhibition in JAK/STAT hyperactive LGL cells. This is of special interest as constitutive STAT activation is observed in almost all LGL proliferations regardless of the presence of mutations in the STAT3 gene.…”