The root of many evils: indolent large granular lymphocyte leukaemia and associated disorders

Zhang, Ranran; Shah, Mithun Vinod; Loughran, Thomas P.

doi:10.1002/hon.917

Cited by 77 publications

(79 citation statements)

References 159 publications

(216 reference statements)

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“…7,8,17,64 Systemic lupus erythematosus, Sjogren syndrome, autoimmune thyroid disorders, coagulopathy, vasculitis with cryoglobulinemia, and inclusion body myositis have occasionally been reported. [64][65][66][67] Pulmonary artery hypertension has been observed. 68 Association with myeloid malignancies and BM failure syndromes, ie, aplastic anemia (AA), paroxysmal nocturnal hemoglobinuria, and MDS, is also reported.…”

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confidence: 99%

LGL leukemia: from pathogenesis to treatment

Lamy

Moignet

Loughran

2017

Blood

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251

391

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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.

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confidence: 99%

LGL leukemia: from pathogenesis to treatment

Lamy

Moignet

Loughran

2017

Blood

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251

391

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“…Upon activation, NK cells proliferate and exert effector functions including perforin-mediated cytotoxicity against target cells and cytokine production such as IFN (IFN)-γ (1). In contrast to the pivotal role of NK cells in host defense, persistent expansion of activated NK cells in benign and malignant conditions is often associated with systemic autoimmune diseases (2)(3)(4). Therefore, NK cells themselves must be regulated after activation.…”

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confidence: 99%

Fratricide of natural killer cells dressed with tumor-derived NKG2D ligand

Nakamura

Nakayama

Kawano

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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The natural killer group 2 membrane D (NKG2D) activating receptor plays crucial roles not only in host defense against tumors and viral infections, but also in autoimmune diseases. After NKG2D-mediated activation, Natural killer (NK) cells must be regulated to avoid potentially harmful reactivity. However, the negative regulation of these activated NK cells is poorly understood. Here, we reveal that the engagement of NKG2D by its ligand elicits not only target cell lysis, but also NK cell fratricide. Conventional mouse NK cells underwent cell death when cocultured with RMA cells expressing the NKG2D ligand retinoic acid early-inducible protein 1 (Rae-1), but not with RMA cells lacking MHC class I. NK cells from mice deficient for DAP10 and DAP12 or perforin did not undergo death, highlighting the importance of the NKG2D pathway for NK cell death. However, NKG2D does not transmit direct death signals in NK cells. Rather, the interaction between NKG2D and Rae-1 allowed NK cells to acquire tumor-derived Rae-1 by a membrane transfer process known as "trogocytosis," which was associated with clathrin-dependent NKG2D endocytosis. NK cells dressed with Rae-1 were lysed by neighboring NK cells through the NKG2D-induced perforin pathway in vitro and in vivo. These results provide the unique NKG2D function in negative regulation of activated NK cells.

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“…However, a significant fraction will develop neutropenia, anemia, recurrent bacterial infections, autoimmune disorders, or symptomatic splenomegaly. 19 Neutropenia, the most common hematologic disorder associated with T-LGL leukemia, is the major reason for these patients seeking medical attention. 18 Approximately 70% to 80% patients with T-LGL leukemia develop neutropenia and may be predisposed to infection.…”

Section: Introductionmentioning

confidence: 99%

Increased serum soluble IL-15Rα levels in T-cell large granular lymphocyte leukemia

Chen

Petrus

Bamford³

et al. 2012

Blood

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IntroductionIL-15 is a proinflammatory cytokine that stimulates T and natural killer (NK) cell activity and induces the expression of TNF-␣, IL-1␤, and other inflammatory chemokines. 1-4 IL-15 is important for the maintenance of long-lasting, high-avidity T-cell responses directed at invading pathogens by supporting the survival of CD8 ϩ memory T cells. In addition, IL-15 also inhibits IL-2-induced activation-induced cell death. 5-7 IL-15 signals through the heterotrimeric IL-15 receptor that includes a private IL-15-specific receptor subunit IL-15R␣, the IL-2/IL-15R␤ subunit (CD122) that is also shared with the IL-2 receptor, and the common ␥-chain (␥ c ) receptor that is shared by IL-2, IL-4, IL-7, IL-9, and IL-21. 3,8 IL-15 binds to IL-15R␣ with high affinity (K d of ϳ 1 ϫ 10 Ϫ11 M). 9 Under physiologic conditions, IL-15 does not act as a secreted molecule but rather is trans-presented on the cell surface of activated monocytes and dendritic cells as part of an immunologic synapse to T and NK cells that express IL-2/IL15R␤ and ␥ c . 10 Abnormalities of IL-15 expression have been implicated in many autoimmune disorders, including rheumatoid arthritis, 11 psoriasis, 12 celiac disease, 13 inflammatory bowel disease, 14 and multiple sclerosis, 15 as well as in select lymphoid malignancies and diseases associated with human T-cell lymphotropic virus 1 infection. 16 In celiac disease, abnormal expression of IL-15R␣ was found to be associated with abnormal IL-15 expression, and together they contribute to the pathogenesis of the disease. 17 This highlights the importance of IL-15R␣ for the function of IL-15.Large granular lymphocyte (LGL) leukemia represents a spectrum of lymphoproliferative diseases that are characterized by abnormal clonal expansions of mature T or NK cells. 18 Based on the cellular origin, LGL leukemia can be divided into T-cell LGL leukemia and NK-cell LGL leukemia. The majority of patients with T-cell LGL leukemia have a clinically indolent course. However, a significant fraction will develop neutropenia, anemia, recurrent bacterial infections, autoimmune disorders, or symptomatic splenomegaly. 19 Neutropenia, the most common hematologic disorder associated with T-LGL leukemia, is the major reason for these patients seeking medical attention. 18 Approximately 70% to 80% patients with T-LGL leukemia develop neutropenia and may be predisposed to infection. Anemia is the second most common hematologic disorder associated with T-LGL leukemia. Another common association is autoimmunity, with rheumatoid arthritis occurring most often. 20,21 Rheumatoid arthritis has been reported in approximately one-third of T-LGL leukemia patients. Although it has been suggested that LGL leukemic cells represent cytotoxic T lymphocytes activated by chronic antigenic stimulation, the molecular mechanisms that lead to LGL leukemia are unknown. The wide association of LGL leukemia with hematologic and autoimmune disorders suggests the possibility of a common pathogenesis in LGL leukemia and their hematologic disorders ...

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The root of many evils: indolent large granular lymphocyte leukaemia and associated disorders

Cited by 77 publications

References 159 publications

LGL leukemia: from pathogenesis to treatment

LGL leukemia: from pathogenesis to treatment

Fratricide of natural killer cells dressed with tumor-derived NKG2D ligand

Increased serum soluble IL-15Rα levels in T-cell large granular lymphocyte leukemia

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