High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia

Andersson, Emma; Tanahashi, Takahiro; Sekiguchi, Nodoka; Gasparini, Vanessa Rebecca; Bortoluzzi, Sabrina; Kawakami, Toru; Matsuda, Kazuyuki; Mitsui, Takeki; Eldfors, Samuli; Bortoluzzi, Stefania; Coppe, Alessandro; Binatti, Andrea; Lagström, Sonja; Ellonen, Pekka; Fukushima, Noriyasu; Nishina, Sayaka; Senoo, Noriko; Sakai, Hitoshi; Nakazawa, Hayakazu; Kwong, Yok Lam; Loughran, Thomas P.; Maciejewski, Jaroslaw P.; Mustjoki, Satu; Ishida, Fumihiro

doi:10.1182/blood-2016-06-724856

Cited by 93 publications

(97 citation statements)

References 18 publications

(22 reference statements)

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“…Up to 72% of patients that are diagnosed with T-cell large granular lymphocyte (T-LGL) leukemia carry SH2-domain mutations in the Stat3 gene, primarily Y640F GOF mutations [155], with alterations at this site being associated with chronic upregulation of Irf7, Irf9, Ifngr2, and Bcl2l1 genes, suppression of the NFκB negative regulator Birc3, cytopenia, and errant myeloproliferation [3,156]. Similarly, Stat5b mutations have been linked to CD4 + T-LGL oncogenesis, with aberrant CD4 + T cell expansion being detected in up to 55% of patients [157]. In myeloproliferative cancer, the JAK2 V617F mutation is associated with significantly lower cumulative survival, whereby individuals harboring the mutation had a three-fold increased risk of early death as compared to individuals negative for JAK2 V617F [158].…”

Section: Dysregulation Of Jak-stat Signaling In Cancermentioning

confidence: 99%

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Owen

Brockwell

Parker

2019

Cancers

439

326

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Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations.2 of 26 role in pathogenesis [3]. Yet, despite the seemingly linear order of events, the impact of mutations, selective dimerization, negative pathway regulation, and post-translational modifications of pathway members has branded the JAK-STAT axis a complex signaling cascade, of which many regulatory processes are still poorly understood.STATs have emerged as somewhat of a double-edged sword, being widely explored in the context of cancer. While several members of the STAT family, which encompasses STAT1, STAT2, STAT3, STAT4, STAT5A, STAT5B, and STAT6 as a whole, have been linked to tumor initiation and progression (STAT3 and STAT5), others are integral in antitumor defense and the maintenance of an effective and long-term immune response (STAT1 and STAT2) through evolutionarily conserved programs [1]. With increasing emphasis on immune-based agents as important therapeutics in the fight against solid tumor growth and spread, understanding the function of STAT specificity, redundancy, and connectedness in cancer is a critical component of achieving immunotherapeutic augmentation and success.Here, we investigate the good and the bad of STAT signaling in the context of immune regulation and cancer, and discuss how STATs can be targeted to bolster antitumor immune defense. JAK-STAT Signaling and InterferonsThe presence of stimulatory or inhibitory signals governs the innate and adaptive immune activity that controls both effective immune surveillance and facilitates escape. Such signals determine the fate of plastic immune cells, such as T lymphocytes, and regulate their recruitment, survival, status, and eventual death ...

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Section: Dysregulation Of Jak-stat Signaling In Cancermentioning

confidence: 99%

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

Owen

Brockwell

Parker

2019

Cancers

439

326

View full text Add to dashboard Cite

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“…23 Recently, it was found that Stat5b mutations are frequent in this LGL subtype. 24 T-LGL leukemic cells are characterized by a terminal-effector memory phenotype defined by the expression of CD45RA and lack of CD62L expression. 25 Leukemic LGL constitutively express interleukin 2 (IL-2) Rb (p75, CD122) and perforin, but not IL-2 Ra (p55, CD25).…”

Section: Epidemiologymentioning

confidence: 99%

LGL leukemia: from pathogenesis to treatment

Lamy

Moignet

Loughran

2017

Blood

Self Cite

244

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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“…Another member of STAT protein family has been reported to carry gain-of-function mutations, namely STAT5b. Initially discovered in only 2% of CD8+ T-LGLL, specifically found in the aggressive form of LGLL (28), STAT5b mutations were subsequently identified in 15-55% of CD4+ T-LGLL (14,15,29), and in 19% of TCRγδ LGLL (15). To date, genetic alterations discovered in STAT5b are all point mutations located in the SH2 and in the transactivation domain of the gene (Figure 1).…”

Section: Stat5b Mutationsmentioning

confidence: 99%

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

et al. 2020

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Large granular lymphocyte leukemia (LGLL) is a chronic proliferation of clonal cytotoxic lymphocytes, usually presenting with cytopenias and yet lacking a specific therapy. The disease is heterogeneous, including different subsets of patients distinguished by LGL immunophenotype (CD8+ Tαβ, CD4+ Tαβ, Tγδ, NK) and the clinical course of the disease (indolent/symptomatic/aggressive). Even if the etiology of LGLL remains elusive, evidence is accumulating on the genetic landscape driving and/or sustaining chronic LGL proliferations. The most common gain-of-function mutations identified in LGLL patients are on STAT3 and STAT5b genes, which have been recently recognized as clonal markers and were included in the 2017 WHO classification of the disease. A significant correlation between STAT3 mutations and symptomatic disease has been highlighted. At variance, STAT5b mutations could have a different clinical impact based on the immunophenotype of the mutated clone. In fact, they are regarded as the signature of an aggressive clinical course with a poor prognosis in CD8+ T-LGLL and aggressive NK cell leukemia, while they are devoid of negative prognostic significance in CD4+ T-LGLL and Tγδ LGLL. Knowing the specific distribution of STAT mutations helps identify the discrete mechanisms sustaining LGL proliferations in the corresponding disease subsets. Some patients equipped with wild type STAT genes are characterized by less frequent mutations in different genes, suggesting that other pathogenetic mechanisms are likely to be involved. In this review, we discuss how the LGLL mutational pattern allows a more precise and detailed tumor stratification, suggesting new parameters for better management of the disease and hopefully paving the way for a targeted clinical approach.

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High incidence of activating STAT5B mutations in CD4-positive T-cell large granular lymphocyte leukemia

Cited by 93 publications

References 18 publications

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression

LGL leukemia: from pathogenesis to treatment

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

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