Activating somatic mutations outside the SH2-domain of STAT3 in LGL leukemia

Andersson, Emma; Kuusanmäki, Heikki; Bortoluzzi, Stefania; Lagström, Sonja; Parsons, Alun; Rajala, Hanna; Adrichem, A. van; Eldfors, Samuli; Olson, Thomas L.; Clemente, Michael J.; Laasonen, A.; Ellonen, Pekka; Heckman, Caroline A.; Loughran, Thomas P.; Maciejewski, Jaroslaw P.; Mustjoki, Satu

doi:10.1038/leu.2015.263

Cited by 67 publications

(53 citation statements)

References 15 publications

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“…All T-LGLL patients are characterized by STAT3 activation, that is the hallmark of every T-LGLL, but a higher amount of the phosphorylated protein has been observed in cases with STAT3 mutations (13,14,17). Functional studies revealed that even if in different locations, most of the reported mutations lead to a higher protein transcriptional activity and cytokine responsiveness (13,27). Nevertheless, deep transcriptional expression studies in T-LGLL did not find significant differences that distinguish patients with and without STAT3 mutations, which showed similar overexpression of STAT3-responsive genes (13,17,28,33).…”

Section: Stat3 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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Section: Stat3 Mutationsmentioning

confidence: 99%

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

et al. 2020

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“…Importantly, recurrent somatic STAT3/5 gain-of-function mutations were found in the SH 2 domain or their extreme C-terminus [126], acting as driver genes predominantly in PTCL. Understanding how mutations within the JAK-STAT pathway alter chromatin via epigenetic changes is key to gaining insight into reprogrammed gene regulation in cancer to tailor patient-specific therapies.…”

Section: Current Therapies and Novel Approachesmentioning

confidence: 99%

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

Orlova

Wingelhofer

Neubauer

et al. 2017

Expert Opinion on Therapeutic Targets

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Introduction: Hematopoietic neoplasms are often driven by gain-of-function mutations of the JAK-STAT pathway together with mutations in chromatin remodeling and DNA damage control pathways. The interconnection between the JAK-STAT pathway, epigenetic regulation or DNA damage control is still poorly understood in cancer cell biology. Areas covered: Here, we focus on a broader description of mutational insights into myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas, since sequencing efforts have identified similar combinations of driver mutations in these diseases covering different lineages. We summarize how these pathways might be interconnected in normal or cancer cells, which have lost differentiation capacity and drive oncogene transcription. Expert opinion: Due to similarities in driver mutations including epigenetic enzymes, JAK-STAT pathway activation and mutated checkpoint control through TP53, we hypothesize that similar therapeutic approaches could be of benefit in these diseases. We give an overview of how driver mutations in these malignancies contribute to hematopoietic cancer initiation or progression, and how these pathways can be targeted with currently available tools.

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“…by guest www.bloodjournal.org From detected. 45 Such mutations are located in the DNA-binding and coiledcoil domain of Stat3. Utilization of deep sequencing has demonstrated the presence of multiple subclones containing different Stat3 mutations in distinct LGL populations in individual patients.…”

Section: Molecular Findingsmentioning

confidence: 99%

LGL leukemia: from pathogenesis to treatment

Lamy

Moignet

Loughran

2017

Blood

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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Activating somatic mutations outside the SH2-domain of STAT3 in LGL leukemia

Cited by 67 publications

References 15 publications

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

Emerging therapeutic targets in myeloproliferative neoplasms and peripheral T-cell leukemia and lymphomas

LGL leukemia: from pathogenesis to treatment

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