Cytokine release by activated T-cells in large granular lymphocytic leukemia associated with autoimmune disorders

Shvidel, Lev; Duksin, Chen; Tzimanis, Alexandra; Shtalrid, Mordechai; Klepfish, Abraham; Sigler, Erica; Haran, Michal; Eilat, Eran; Berrébi, Alain

doi:10.1038/sj.thj.6200149

Cited by 31 publications

(28 citation statements)

References 17 publications

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“…clonal T-LGL cells had elevated phospho-AKT ( Figure 1A, lanes [3][4][5]. In each patient with T-LGL who we have studied thus far, elevated levels of phospho-AKT have been observed.…”

Section: Pi3k Activity In T-lglmentioning

confidence: 98%

“…They appear to represent a paraneoplastic syndrome due to the cytokines released and/or direct killing by the T-LGL clone equipped with a specific T-cell receptor. [3][4][5] While the pathogenesis of T-LGL remains unknown, lack of homeostatic apoptosis is a remarkable feature of this disease since the clonal CTLs abundantly express Fas and Fas ligand (FasL), 2 the most effective pathway for T lymphocyte reduction following resolution of an immune response. 6-10 One potential explanation for this finding is that activation of an opposing survival pathway in T-LGL prevents efficient Fas signaling, thus attenuating apoptotic signals.…”

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confidence: 99%

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Phosphatidylinositol-3-phosphate kinase pathway activation protects leukemic large granular lymphocytes from undergoing homeostatic apoptosis

Schade

Powers

Wlodarski

et al. 2006

Blood

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T-cell large granular lymphocytic leukemia (T-LGL) is characterized by chronic clonal lymphoproliferation of cytotoxic T lymphocytes (CTLs). Despite exhibiting phenotypic properties of antigen-activated cells, including expression of Fas and FasL, T-LGL cells accumulate and demonstrate resistance to apoptosis. We propose that increased activity of a prosurvival signaling pathway in T-LGL is responsible for attenuated apoptosis in T-LGL. Given the importance of the phosphatidylinositol-3 kinase (PI3K)-AKT pathway in regulating the balance between survival and apoptosis, we analyzed AKT activity in T-LGL cells. Compared with resting CTLs from healthy donors, patients' T-LGL cells showed higher levels of phosphorylated AKT. We demonstrate that phospho-AKT induction is dependent on the upstream activity of a Src family kinase. Since the PI3K-AKT pathway can antagonize the ability of Fas to initiate apoptosis, we hypothesized that inhibition of PI3K would lead to reacquisition of Fas sensitivity in T-LGL. Inhibition of the PI3K-AKT pathway alone led to brisk spontaneous apoptosis of T-LGL. These results suggest that T-LGL pathogenesis is dependent on activity of the PI3K-AKT pathway, without which the leukemic cells will begin to undergo spontaneous apoptosis. We propose that novel therapeutics inhibiting the PI3K-AKT axis may provide effective treatment for T-LGL.

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“…clonal T-LGL cells had elevated phospho-AKT ( Figure 1A, lanes [3][4][5]. In each patient with T-LGL who we have studied thus far, elevated levels of phospho-AKT have been observed.…”

Section: Pi3k Activity In T-lglmentioning

confidence: 98%

mentioning

confidence: 99%

Phosphatidylinositol-3-phosphate kinase pathway activation protects leukemic large granular lymphocytes from undergoing homeostatic apoptosis

Schade

Powers

Wlodarski

et al. 2006

Blood

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“…Studies have proved that an AID-associated inflammatory cytokine, such as tumor necrosis factor (TNF)-α and interferon-γ, could directly mediate the apoptotic process of myeloid precursor cells resulting in cytopenias, with or without accompanying MDS [46]. Some cytokine releases and clonal T-LGL/NK cell expansion during an autoimmune process could alter tissue microenvironments [47]. If the process occurred in MDS bone marrow, it would cause gene dysregulation in hematopoietic stem cells [27].…”

Section: Discussionmentioning

confidence: 99%

A Close Association of Autoimmune-Mediated Processes and Autoimmune Disorders with Chronic Myelomonocytic Leukemia: Observation from a Single Institution

Peker¹,

Padron²,

Bennett

et al. 2014

Acta Haematol

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Chronic myelomonocytic leukemia (CMML), a clonal hematopoietic stem cell disease, may be linked to immune-mediated processes and/or autoimmune disorders (AID), although the exact pathogens are still elusive. We retrospectively analyzed 123 CMML patients in our institution. Twenty-four CMML patients (19.5%) had at least one immune-mediated disorder, most commonly idiopathic thrombocytopenic purpura, gout and psoriasis. Four of these 24 patients (15%) had more than one AID. We found that, in contrast to the general population with a prevalence rate of 3.2-5.2%, newly diagnosed CMML patients demonstrated a high prevalence and variety of immune-mediated processes and/or AID. When we compared the results with those of myelodysplastic syndromes published in the literature, the prevalence of AID in these two groups of patients is similar. Our results also showed that the presence of cytogenetic abnormalities was less in CMML patients with AID (6 of 21; 28.6%) than in those without AID (37 of 94; 39.4%), although there was no statistical significance (p = 0.334). A multicenter large cohort study of CMML with AID is recommended to illustrate the molecular relationship between the two distinct groups. © 2014 S. Karger AG, Basel

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“…Also, it has been suggested that dendritic cells may be the relevant presenting cell that triggers the clonal proliferation and maintains LGL expansion by cytokine production, in particular IL-15. 29,38 Taken together, these data highlight the importance of tumor environment 39 (ie, ongoing inflammation) in this setting and point out that additional cells, different from the malignant LGL clone, contribute to disease development and maintenance. We also provided evidence that patients' PBMCs release in vivo high amounts of soluble IL-6Ra, allowing…”

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confidence: 97%

Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia

Teramo

Gattazzo

Passeri

et al. 2013

Blood

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Key Points• In T-LGLL, autologous LGLdepleted PBMCs release high levels of IL-6 contributing to the constitutive STAT3 activation in leukemic LGL. • LeukemicLGLs show SOCS3 down-modulation, which is responsible for lack of the negative feedback mechanism controlling STAT3 activation.The JAK/STAT pathway is altered in T-cell large granular lymphocytic leukemia. In all patients, leukemicLGLs display upregulation of phosphorylated STAT3 (P-STAT3) that activates expression of many antiapoptotic genes. To investigate the mechanisms maintaining STAT3 aberrantly phosphorylated using transcriptional protein and functional assays, we analyzed interleukin (IL)-6 and suppressor of cytokine signaling-3 (SOCS3), 2 key factors of the JAK/STAT pathway that induce and inhibit STAT3 activation, respectively. We showed that IL-6 was highly expressed and released by the patients' peripheral blood LGL-depleted population, accounting for a trans-signaling process. By neutralizing IL-6 or its specific receptor with specific antibodies, a significant reduction of P-STAT3 levels and, consequently, LGL survival was demonstrated. In addition, we found that SOCS3 was down-modulated in LGL and unresponsive to IL-6 stimulation. By treating neoplasticLGLs with a demethylating agent, IL-6-mediated SOCS3 expression was restored with consequent P-STAT3 and myeloid cell leukemia-1 down-modulation. Methylation in the SOCS3 promoter was not detectable, suggesting that an epigenetic inhibition mechanism occurs at a different site. Our data indicate that loss of the inhibitor SOCS3 cooperates with IL-6 to maintain JAK/STAT pathway activation, thus contributing to leukemic LGL survival, and suggest a role of demethylating agents in the treatment of this disorder. (Blood. 2013;121(19):3843-3854)

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Cytokine release by activated T-cells in large granular lymphocytic leukemia associated with autoimmune disorders

Abstract: Our findings showing the potential of LGLL cells for cytokine release in vitro suggests that these cells may play a major role in the immune disturbances observed in large granular lymphocytic leukemia accompanied by autoimmunity features.

Cited by 31 publications

References 17 publications

Phosphatidylinositol-3-phosphate kinase pathway activation protects leukemic large granular lymphocytes from undergoing homeostatic apoptosis

Phosphatidylinositol-3-phosphate kinase pathway activation protects leukemic large granular lymphocytes from undergoing homeostatic apoptosis

A Close Association of Autoimmune-Mediated Processes and Autoimmune Disorders with Chronic Myelomonocytic Leukemia: Observation from a Single Institution

Intrinsic and extrinsic mechanisms contribute to maintain the JAK/STAT pathway aberrantly activated in T-type large granular lymphocyte leukemia

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