Somatic<i>STAT3</i>Mutations in Large Granular Lymphocytic Leukemia

Koskela, Hanna; Eldfors, Samuli; Ellonen, Pekka; Adrichem, Arjan J. van; Kuusanmäki, Heikki; Andersson, Emma; Lagström, Sonja; Clemente, Michael J.; Olson, Thomas L.; Jalkanen, S.; Majumder, Muntasir Mamun; Almusa, Henrikki; Edgren, Henrik; Lepistö, Maija; Mattila, Pirkko; Guinta, Kathryn; Koistinen, Pirjo; Kuittinen, Taru; Penttinen, Kati; Parsons, Alun; Knowles, Jonathan; Saarela, Janna; Wennerberg, Krister; Kallioniemi, Olli; Porkka, Kimmo; Loughran, Thomas P.; Heckman, Caroline A.; Maciejewski, Jaroslaw P.; Mustjoki, Satu

doi:10.1056/nejmoa1114885

Cited by 703 publications

(708 citation statements)

References 36 publications

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“…During T cell‐large granular lymphocytic leukemia (T‐LGL leukemia) clonally expanded large granular CD8 + CD57 + CTLs can be found in peripheral blood, spleen and bone marrow 96. Interestingly, a recent study describes a previously undiscovered association between IBM and T‐LGL leukemia 97.…”

Section: Pathomechanisms In Ibmmentioning

confidence: 99%

Immune and myodegenerative pathomechanisms in inclusion body myositis

Keller

Schmidt

Lünemann

2017

Ann Clin Transl Neurol

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Inclusion Body Myositis (IBM) is a relatively common acquired inflammatory myopathy in patients above 50 years of age. Pathological hallmarks of IBM are intramyofiber protein inclusions and endomysial inflammation, indicating that both myodegenerative and inflammatory mechanisms contribute to its pathogenesis. Impaired protein degradation by the autophagic machinery, which regulates innate and adaptive immune responses, in skeletal muscle fibers has recently been identified as a potential key pathomechanism in IBM. Immunotherapies, which are successfully used for treating other inflammatory myopathies lack efficacy in IBM and so far no effective treatment is available. Thus, a better understanding of the mechanistic pathways underlying progressive muscle weakness and atrophy in IBM is crucial in identifying novel promising targets for therapeutic intervention. Here, we discuss recent insights into the pathomechanistic network of mutually dependent inflammatory and degenerative events during IBM.

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Section: Pathomechanisms In Ibmmentioning

confidence: 99%

Immune and myodegenerative pathomechanisms in inclusion body myositis

Keller

Schmidt

Lünemann

2017

Ann Clin Transl Neurol

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“…These mutations seem to activate the downstream STAT3 pathway and the patients present more often with neutropenia and rheumatoid arthritis. 97 How all this expanding information may be translated into clinical practice is difficult to foresee at the present time. It is still too early to start making predictions but it seems, from the functional and clinical studies already performed for some of the genes, that this new information will have an important impact.…”

Section: Landscape Of Somatic Mutations In Lymphoid Neoplasmsmentioning

confidence: 99%

Whole genome profiling and other high throughput technologies in lymphoid neoplasms—current contributions and future hopes

Campo

2013

Modern Pathology

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The development of high throughput technologies based on the knowledge of the human genome has opened the possibility to search for global genomic alterations in tumors responsible for their development and progression that may have important clinical implications. One of the major applications of this genomic knowledge has been the design of different types of microarray platforms for the analysis of DNA alterations and gene expression profiling (GEP). The main contributions of the DNA studies in lymphoid neoplasms include the definition of relatively characteristic genomic profiles for specific disease entities, the demonstration of common chromosomal alterations across entities, the identification of genes and pathways targeted by the altered chromosomal regions, and the identification of chromosomal alterations with prognostic implications. RNA GEP studies in these tumors have enhanced the molecular characterization of known entities and facilitated the recognition of new subtypes and categories of lymphoid neoplasms, the identification of new biomarkers and prognostic models, and the detection of oncogenic pathways with potential implications for targeted therapies. The recent development of the next generation sequencing (NGS) technologies and its application in lymphoid neoplasms already have provided an initial view of the complex landscape of somatic mutations in these tumors and some findings with important functional and clinical implications. This review addresses the major contributions and limitations of the microarray technologies in the understanding of lymphoid neoplasms and discusses how this knowledge may be transferred into the clinics. The initial results of the NGS studies are also presented.

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“…Signal transducers and activators of transcription 3 (STAT3), a major component of the STAT family, has been established to play important roles in the development and progression of many human malignancies, such as glioma, pancreatic cancer, prostate cancer, anaplastic large cell lymphoma, and T-cell large granular lymphocyte leukemia (7)(8)(9)(10). Phosphorylation of STAT3 triggers its dimerization and nuclear transport, where it promotes the transcription of genes that stimulate tumor growth.…”

Section: Introductionmentioning

confidence: 99%

WP1066 exhibits antitumor efficacy in nasal-type natural killer/T-cell lymphoma cells through downregulation of the STAT3 signaling pathway

Geng

Zhou

et al. 2016

Oncology Reports

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Abstract. Nasal-type natural killer/T-cell lymphoma (nasal NKTCL) is an aggressive hematological neoplasm with poor prognosis, and its incidence is higher in Asia than in Western countries. Increasing evidence suggests that aberrant activation of signal transducers and activators of transcription 3 (STAT3) is related to numerous malignancies. However, the involvement of STAT3 in the pathogenesis of nasal NKTCL is poorly understood. In this study, immunohistochemistry (IHC) showed that 21/28 (75.0%) nasal NKTCL tissues harbored constitutively expression of phospho-STAT3 (p-STAT3) which was positively correlated with the Ki-67 levels (P﹤0.05). Immunofluorescence (IF) also detected p-STAT3 expression in SNK6 cells (NKTCL cell line). Furthermore, WP1066 (a novel selective STAT3 inhibitor) was able to inhibit proliferation and induce apoptosis of SNK6 cells. Moreover, western blot analysis and RT-PCR demonstrated that WP1066 downregulated the protein and mRNA expressions of the pro-survival molecules (including c-Myc, cyclin D1, and Bcl-2) in SNK6 cells. These results suggested that STAT3 activation represents a potential target in nasal NKTCL. WP1066 may be a promising agent in antitumor therapy against nasal NKTCL.

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SomaticSTAT3Mutations in Large Granular Lymphocytic Leukemia

Cited by 703 publications

References 36 publications

Immune and myodegenerative pathomechanisms in inclusion body myositis

Immune and myodegenerative pathomechanisms in inclusion body myositis

Whole genome profiling and other high throughput technologies in lymphoid neoplasms—current contributions and future hopes

WP1066 exhibits antitumor efficacy in nasal-type natural killer/T-cell lymphoma cells through downregulation of the STAT3 signaling pathway

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