Targetability of STAT3-JAK2 fusions: implications for T-cell lymphoproliferative disorders of the gastrointestinal tract

Hu, Guojie; Phillips, Jessica; Dasari, Surendra; Jacobs, Hailey K.; Luchtel, Rebecca A.; Oishi, Naoki; Hundal, Tanya; Ahmed, Nada; Satou, Akira; Epstein, Alan L.; Bennani, N. Nora; Nowakowski, Grzegorz S.; Murray, Joseph A.; Feldman, Andrew L.

doi:10.1038/s41375-019-0678-3

Cited by 7 publications

(6 citation statements)

References 14 publications

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“…Importantly, a recent study by Hu et al ectopically expressed STAT3-JAK2 in different cell types, and showed that STAT3 is marginally phosphorylated, and have transcriptional activity albeit to a lesser extent than that of STAT5. Of note, STAT3-JAK2 fusion protein was observed to bind to and phosphorylate STAT5 much efficiently, consistent with the observation that STAT5 target genes were enriched in STAT3-JAK2 transduced T cell breast lymphoma 3 (TLBR3) cells but not STAT3 (22). The observed discrepancy related to STAT3 activation status may be due to relatively lower sensitivity of immunohistochemistry compared to that of western blot, high level of expression of phosphatases that dephosphorylate STAT3, or the intracellular amount of available STAT3 protein in indolent GI T-LPD cells.…”

Section: Discovered Genetic Alterations To Avoid Indolent Gi T-lpd MIsupporting

confidence: 82%

Indolent T-Cell Lymphoproliferative Disease of the GI Tract: Insights for Better Diagnosis, Prognosis, and Appropriate Therapy

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You

2020

Front. Oncol.

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Section: Discovered Genetic Alterations To Avoid Indolent Gi T-lpd MIsupporting

confidence: 82%

Indolent T-Cell Lymphoproliferative Disease of the GI Tract: Insights for Better Diagnosis, Prognosis, and Appropriate Therapy

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You

2020

Front. Oncol.

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“…Frequent oncogenic activation of the JAK/STAT signaling pathway may be an attractive therapeutic target (Figure 5). 278,294,295 Distinctive genomic features help differentiate between enteropathy-associated T-cell lymphoma (EATL), monomorphic epitheliotropic T-cell lymphoma (MEITL), and indolent T/NK LPDs of the gastrointestinal tract (Table 3). Alterations in the JAK/ STAT pathway genes primarily target STAT3 and JAK1 in EATL and STAT5B and JAK3 in MEITL; a recurrent deletion in JAK3 characterizes some indolent gastrointestinal NK LPDs, 296 and a proportion of indolent clonal T-cell LPDs of the gastrointestinal tract harbor hotspot STAT3 mutations or JAK2::STAT3 fusion.…”

Section: Extranodal Ptclsmentioning

confidence: 99%

Genomic profiling for clinical decision making in lymphoid neoplasms

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Alizadeh

Bergsagel

et al. 2022

Blood

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With the introduction of large-scale molecular profiling methods and high-throughput sequencing technologies, the genomic features of most lymphoid neoplasms have been characterized at an unprecedented scale. While the principles for the classification and diagnosis of these disorders, founded on a multidimensional definition of disease entities, have been consolidated over the past 25 years, novel genomic data have markedly enhanced our understanding of lymphomagenesis and enriched the description of disease entities at the molecular level. Yet the current diagnosis of lymphoid tumors is largely based on morphological assessment and immunophenotyping, with only few entities being defined by genomic criteria. This paper, which accompanies the International Consensus Classification of mature lymphoid neoplasms, will address how established assays and newly developed technologies for molecular testing already complement clinical diagnoses and provide a novel lens on disease classification. More specifically, their contributions to diagnosis refinement, risk stratification and therapy prediction will be considered for the main categories of lymphoid neoplasms. The potential of whole-genome sequencing, circulating tumor DNA analyses, single-cell analyses and epigenetic profiling will be discussed, as these will likely become important future tools for implementing precision medicine approaches in clinical decision-making for patients with lymphoid malignancies.

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“…Similar to the previously reported fusions, the STAT3 ‐ JAK2 rearrangement in BIA‐ALCL retains the entire catalytic domain (JH1) of JAK2 and shares the same STAT3 RNA breakpoint. Recent functional studies performed by Hu et al, confirm this fusion to be oncogenic both in vitro and in‐vivo using various models 26 …”

Section: Discussionmentioning

confidence: 87%

“…Studies also demonstrated that fusion expression activates STAT5 and constitutively enhances transcriptional activity within the JAK ‐ STAT pathway. More importantly, preliminary work by the same group using various JAK inhibitors in‐vitro and in an animal model characterize this fusion as a potential targetable event with differential impact on the activity of the fusion protein 26 …”

Section: Discussionmentioning

confidence: 99%

Next generation sequencing of breast implant‐associated anaplastic large cell lymphomas reveals a novel STAT3‐JAK2 fusion among other activating genetic alterations within the JAK‐STAT pathway

et al. 2021

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Breast implant associated anaplastic large cell lymphoma (BIA‐ALCL) is a distinct type of ALCL, and a new provisional entity by the 2016 revision of the World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues. In contrast to systemic and primary cutaneous ALCLs, BIA‐ALCLs have been genetically characterized by the absence of fusions and frequent activation of the JAK‐STAT3 pathway through mutations in JAK1 and STAT3. In this study, we report the results of the genetic profiling of 9 BIA‐ALCL cases supporting the role of the JAK‐STAT pathway activation in this entity, including the identification of an activating STAT3‐JAK2 fusion similar to those recently reported in T‐cell lymphoproliferative disorders of the gastrointestinal tract. To our knowledge, this is the first fusion reported in BIA‐ALCL, providing further insight into the overall genetic landscape of this rare entity as well as uncovering potential options for targeted therapy in cases with advanced disease.

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Targetability of STAT3-JAK2 fusions: implications for T-cell lymphoproliferative disorders of the gastrointestinal tract

Cited by 7 publications

References 14 publications

Indolent T-Cell Lymphoproliferative Disease of the GI Tract: Insights for Better Diagnosis, Prognosis, and Appropriate Therapy

Indolent T-Cell Lymphoproliferative Disease of the GI Tract: Insights for Better Diagnosis, Prognosis, and Appropriate Therapy

Genomic profiling for clinical decision making in lymphoid neoplasms

Next generation sequencing of breast implant‐associated anaplastic large cell lymphomas reveals a novel STAT3‐JAK2 fusion among other activating genetic alterations within the JAK‐STAT pathway

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