Recurrent STAT3-JAK2 fusions in indolent T-cell lymphoproliferative disorder of the gastrointestinal tract

Sharma, Ayush; Oishi, Naoki; Boddicker, Rebecca L.; Hu, Guojie; Benson, Hailey K.; Ketterling, Rhett P.; Greipp, Patricia T.; Knutson, Darlene L.; Kloft‐Nelson, Sara M.; He, Rong; Eckloff, Bruce W.; Jen, Jin; Nair, Asha; Davila, Jaime; Dasari, Surendra; Lazaridis, Konstantinos N.; Bennani, N. Nora; Wu, Tsung Teh; Nowakowski, Grzegorz S.; Murray, Joseph A.; Feldman, Andrew L.

doi:10.1182/blood-2018-01-830968

Cited by 79 publications

(124 citation statements)

References 23 publications

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“…The clinical presentations and disease course of our patients were largely congruent with previous descriptions 6, [8][9][10][11][12][13][14][15][16] . Of interest, the ITLPDs were detected incidentally in two asymptomatic patients, which has rarely been documented 10 .…”

Section: Discussionsupporting

confidence: 90%

“…Deletion of SOCS1, a negative regulator of the JAK family proteins 30 , which was seen in a colonic CD4+ ITLPD, is a recurrent abnormality in a variety of T-cell lymphomas and more commonly reported in mycosis fungoides 31 . We confirm the STAT3-JAK2 rearrangement to be a recurrent event in CD4+ ITLPDs, however, this alteration was only observed in one (25%) of our cases compared to 4/5 (80%) cases in the series of Sharma et al 15 .…”

Section: Discussionsupporting

confidence: 71%

“…Overlapping genomic and genetic alterations have been reported in EATL and MEITL [17][18][19][20][21] . Limited data suggest a different spectrum of genomic aberrations in ITLPDs of the GI tract 11, 13 , and until recently, no recurrent genetic abnormality had been identified in these disorders 15 . However, the mutational landscape and molecular pathways underlying the initiation and progression of ITLPDs of the GI tract are unknown and the cell of origin of the different immunophenotypic subsets has not been defined.…”

Section: Introductionmentioning

confidence: 99%

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Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract

et al. 2019

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Indolent T-cell lymphoproliferative disorders of the gastrointestinal tract are rare clonal T-cell diseases that more commonly occur in the intestines and have a protracted clinical course. Different immunophenotypic subsets have been described, but the molecular pathogenesis and cell of origin of these lymphocytic proliferations is poorly understood. Hence, we performed targeted next-generation sequencing and comprehensive immunophenotypic analysis of 10 indolent T-cell lymphoproliferative disorders of the gastrointestinal tract, which comprised CD4+ (n=4), CD8+ (n=4), CD4+/CD8+ (n=1) and CD4-/CD8-(n=1) cases. Genetic alterations, including recurrent mutations and novel rearrangements, were identified in 8/10 (80%) lymphoproliferative disorders. The CD4+, CD4+/CD8+, and CD4-/CD8-cases harbored frequent alterations of the JAK-STAT pathway genes (5/6, 82%); STAT3 mutations (n=3), SOCS1 deletion (n=1) and STAT3-JAK2 rearrangement (n=1), and 4/6 (67%) had concomitant mutations in epigenetic modifier genes (TET2, DNMT3A, KMT2D). Conversely, 2/4 (50%) of the CD8+ cases exhibited structural alterations involving the 3' untranslated region of the IL2 gene. Longitudinal genetic analysis revealed stable mutational profiles in 4/5 (80%) cases and acquisition of mutations in one case were a harbinger of disease transformation. The CD4+ and CD4+/CD8+ lymphoproliferative disorders displayed heterogeneous Th1 (T-bet+), Th2 (GATA3+) or hybrid Th1/Th2 (T-bet+/GATA3+) profiles, while the majority of CD8+ disorders and the CD4-/CD8-disease showed a type-2 polarized (GATA3+) effector T-cell (Tc2) phenotype. Additionally, CD103 expression was noted in 2/4 CD8+ cases. Our findings provide insights into the pathogenetic bases of indolent T-cell lymphoproliferative disorders of the 4 gastrointestinal tract and confirm the heterogeneous nature of these diseases.Detection of shared and distinct genetic alterations of the JAK-STAT pathway in certain immunophenotypic subsets warrants further mechanistic studies to determine whether therapeutic targeting of this signaling cascade is efficacious for a proportion of patients with these recalcitrant diseases.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 71%

Section: Introductionmentioning

confidence: 99%

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Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract

et al. 2019

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“…STAT3 mutations (or evidence of STAT3 activation) were not observed in a series largely comprising CD8+ LPDs. Recently, however, recurrent STAT3‐JAK2 fusions have been identified by next‐generation sequencing and FISH analysis in 4 of 5 CD4+ LPDs …”

Section: Intestinal T‐cell Lymphomasmentioning

confidence: 99%

Breast implant‐associated anaplastic large cell lymphoma and other rare T‐cell lymphomas

Leval

2019

Hematological Oncology

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Peripheral T-cell lymphomas (PTCLs) account for less than 15% of all non-Hodgkin lymphomas worldwide. In the current WHO classification, more than 25 types of T-cell neoplasms are listed (Table 1). 1 Considering the noncutaneous T-cell lymphomas, despite substantial geographic variations in the incidence and the subtype prevalence, a few entities-essentially those presenting as nodal diseases-are relatively common and account for the majority of the cases, while extranodal entities are far less common or distinctively rare. Here, we will review the clinico-pathological features of breast implant (BI)-associated anaplastic large cell lymphoma and intestinal T-cell neoplasms, with a focus on the recent advances in the understanding of their molecular biology and pathogenesis. 2 | BREAST IMPLANT-ASSOCIATED ANAPLASTIC LARGE CELL LYMPHOMA Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a very rare form of T-cell lymphoma that arises in association with BIs. BIA-ALCL was introduced as a new provisional disease entity in the recently revised WHO classification of lymphoid malignancies, distinct from the other types of ALCLs already recognized (anaplastic lymphoma kinase [ALK]-positive and ALK-negative ALCL and primary cutaneous ALCL). 1 2.1 | Epidemiology Since the first case was described in 1997, more than 500 cases of BIA-ALCL have been reported in the literature worldwide. An increasing number of dioagnoses were recorded over the recent years reflecting a substantial increase in recognition and awareness of the disease. Notwithstanding these trends, the incidence of BIA-ALCL remains very low. Primary breast lymphomas represent 1% to 2% of all non-Hodgkin lymphomas, with most cases diagnosed as diffuse large B-cell lymphomas, follicular or marginal zone B-cell lymphomas. Among more than 400 breast lymphomas accumulated between 2010 and 2018 in the French lymphoma network, BIA-ALCL represented 10% of the diagnoses. 2Taking into consideration the very large number of women with BIs over the world, the individual risk of BIA-ALCL is very small. A recent population-based case-control study based on the pathology registry in the Netherlands established that BI is associated with a markedly increased risk (400 times) of developing ALCL, but the absolute cumulative risk is estimated to one case for every 50 000 women with BI by the age of 50 years and one per 7000 by the age of 75. 2 In another study based on US cases, the lifetime risk of BIA-ALCL in women with textured implants was estimated to be 1 in 30 000. 3 | Clinical featuresThe mean age at diagnosis is in the 50s. Approximately 60% of women who develop BIA-ALCL had implants for cosmetic reasons, and 40% had implants for reconstructive purposes after surgery for breast cancer. BIA-ALCL has also been reported in three transgender male to female individuals. The median time interval between implant insertion and lymphoma diagnosis is 8 to 9 years in different studies, but wide variations are observed. There is no significant difference in risk o...

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“…As Stat3 was previously demonstrated to function as a transcriptional activator (Sharma, et al,2018), we designed a luciferase reporter assay to determine if Stat3 is also act to regulate Nav1.7-Nav1.9 transcription. Scn9a-Scn11a promoter regions (relative to the transcription start site) were cloned into a luciferase reporter vector (pGL3 Basic plasmid) such that luciferase expression is driven by the Scn9a-Scn11a promoter sequences.…”

Section: Jak2-stat3 Signaling Pathway Is Involved In Gm-csf Induced Umentioning

confidence: 99%

Transcriptional regulation of voltage-gated sodium channels contributes to GM-CSF induced pain

Zhang

Wang

Zhang

et al. 2018

Preprint

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Granolocyte-macrophage colony stimulating factor (GM-CSF) induces production of granulocyte and macrophage populations from the hematopoietic progenitor cells; it is one of the most common growth factors in the blood. GM-CSF is also involved in bone cancer pain development by regulating tumor-nerve interactions, remodeling of peripheral nerves and sensitization of damage-sensing (nociceptive) nerves. However, the precise mechanism for GM-CSF-dependent pain is unclear. In this study, we found that GM-CSF is highly expressed in human malignant osteosarcoma. Rats implanted with bone cancer cells develop mechanical and thermal hyperalgesia but antagonizing GM-CSF in these animals significantly reduced such hypersensitivity.Nociceptor-specific voltage gated Na + channels Nav1.7, Nav1.8 and Nav1.9 were found to be selectively up-regulated in rat DRG neurons treated with GM-CSF, which resulted in enhanced excitability. GM-CSF activated the Jak2 and Stat3 signaling pathway which promoted the transcription of Nav1.7-1.9 in DRG neurons.Accordingly targeted knocking down either Nav1.7-1.9 or Jak2/Stat3 in DRG neurons alleviated the hyperalgesia in rats. Our findings describe a new bone cancer pain mechanism and provide a new insight into the physiological and pathological functions of GM-CSF.

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Recurrent STAT3-JAK2 fusions in indolent T-cell lymphoproliferative disorder of the gastrointestinal tract

Cited by 79 publications

References 23 publications

Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract

Genetic and phenotypic characterization of indolent T-cell lymphoproliferative disorders of the gastrointestinal tract

Breast implant‐associated anaplastic large cell lymphoma and other rare T‐cell lymphomas

Transcriptional regulation of voltage-gated sodium channels contributes to GM-CSF induced pain

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