Mutations in the JAK/STAT and RAS signaling pathways are common in intestinal T-cell lymphomas

Nicolae, Alina; Xi, Liqiang; Pham, Ta; Navarro, Winnifred; Meeker, H G; Pittaluga, Stefania; Jaffe, Elaine S.; Raffeld, Mark

doi:10.1038/leu.2016.178

Cited by 79 publications

(77 citation statements)

References 14 publications

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“…Mutations of genes encoding for components of the JAK/STAT pathway are frequently found in T-cell neoplasms (predominantly mutations of JAK3, STAT3, and STAT5B). Their reported incidences range from 10% (e.g., for Sézary syndrome [29]) to 70% (e.g., for intestinal T-cell lymphoma [30]). Compared to those, the cumulative mutation frequency of JAK and STAT genes in T-PLL documented in this meta-analysis is high [31].…”

Section: Discussionmentioning

confidence: 99%

JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL

Wahnschaffe

Braun

Timonen

et al. 2019

Cancers

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T-cell prolymphocytic leukemia (T-PLL) is a rare and poor-prognostic mature T-cell leukemia. Recent studies detected genomic aberrations affecting JAK and STAT genes in T-PLL. Due to the limited number of primary patient samples available, genomic analyses of the JAK/STAT pathway have been performed in rather small cohorts. Therefore, we conducted-via a primary-data based pipeline-a meta-analysis that re-evaluated the genomic landscape of T-PLL. It included all available data sets with sequence information on JAK or STAT gene loci in 275 T-PLL. We eliminated overlapping cases and determined a cumulative rate of 62.1% of cases with mutated JAK or STAT genes. Most frequently, JAK1 (6.3%), JAK3 (36.4%), and STAT5B (18.8%) carried somatic single-nucleotide variants (SNVs), with missense mutations in the SH2 or pseudokinase domains as most prevalent. Importantly, these lesions were predominantly subclonal. We did not detect any strong association between mutations of a JAK or STAT gene with clinical characteristics. Irrespective of the presence of gain-of-function (GOF) SNVs, basal phosphorylation of STAT5B was elevated in all analyzed T-PLL. Fittingly, a significant proportion of genes encoding for potential negative regulators of STAT5B showed genomic losses (in 71.4% of T-PLL in total, in 68.4% of T-PLL without any JAK or STAT mutations). They included DUSP4, CD45, TCPTP, SHP1, SOCS1, SOCS3, and HDAC9.Overall, considering such losses of negative regulators and the GOF mutations in JAK and STAT genes, a total of 89.8% of T-PLL revealed a genomic aberration potentially explaining enhanced STAT5B activity. In essence, we present a comprehensive meta-analysis on the highly prevalent genomic lesions that affect genes encoding JAK/STAT signaling components. This provides an overview of possible modes of activation of this pathway in a large cohort of T-PLL. In light of new advances in JAK/STAT inhibitor development, we also outline translational contexts for harnessing active JAK/STAT signaling, which has emerged as a 'secondary' hallmark of T-PLL.

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Section: Discussionmentioning

confidence: 99%

JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL

Wahnschaffe

Braun

Timonen

et al. 2019

Cancers

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“…+9q31-qter Frequent +8q24 (MYC) Mutational profile 28,49,64 SETD2 mutation (~15%) JAK/STAT and RAS signalling pathway mutations SETD2 mutation (60-90%) JAK/STAT, RAS and G-protein-coupled receptor signalling pathway mutations Gene expression profile 49 Interferon-g signalling pathway NK-like cytotoxic pathway…”

Section: Immunophenotypementioning

confidence: 99%

“…1,2,5,7,20,27 Limited data suggest that EATL shows variability in T-cell receptor (TCR) expression; a subset expresses TCRb (Beta-F1), 26,28,29 while others express TCRg 28,29 or are receptor silent. 28 EATL is Epstein-Barr virus-encoded RNA (EBER) negative by in situ hybridisation, though admixed EBER+ host small lymphocytes may be evident. 1,2,7 The MIB1/Ki-67 proliferation is high (>50%) in virtually all cases of EATL.…”

Section: Immunophenotypementioning

confidence: 99%

“…46 Recent nextgeneration sequencing studies have shown recurrent mutations involving the JAK/STAT (JAK1, JAK3, STAT3, STAT5B and SOCS1) and RAS (KRAS and NRAS) signalling pathways. 28,49 Furthermore, recurrent loss-of-function mutations of SETD2 may be seen in a minor proportion (approximately 15%) of EATLs. 49 Interestingly, almost all these mutations occur in both EATL and MEITL, albeit with variable frequency.…”

Section: Molecular Geneticsmentioning

confidence: 99%

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T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract: review and update

Vliet

Spagnolo

2020

Pathology

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“…158 The related STAT5B is mutated far less in LGL, but more commonly in T-cell prolymphocytic leukemia 159 and enteropathy-associated T-cell lymphoma, type II (renamed as monomorphic epitheliotropic intestinal T-cell lymphoma [MEITL] in the 2016 WHO revision). [160][161][162] Both STAT3 and STAT5B are also mutated in gd-hepatosplenic/cutaneous T-cell lymphoma and nasal-type NK-/ T-cell lymphoma 160,163,164 (Table 4). SETD2 mutations were recently identified in up to 90% of MEITL and 25% of gd-hepatosplenic T-cell lymphoma.…”

Section: Mature T/nk Neoplasmsmentioning

confidence: 99%

Diagnosis and classification of hematologic malignancies on the basis of genetics

Taylor¹,

Xiao²,

Abdel-Wahab

2017

Blood

194

149

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Genomic analysis has greatly influenced the diagnosis and clinical management of patients affected by diverse forms of hematologic malignancies. Here, we review how genetic alterations define subclasses of patients with acute leukemias, myelodysplastic syndromes (MDS), myeloproliferative neoplasms (MPNs), non-Hodgkin lymphomas, and classical Hodgkin lymphoma. These include new subtypes of acute myeloid leukemia defined by mutations in RUNX1 or BCR-ABL1 translocations as well as a constellation of somatic structural DNA alterations in acute lymphoblastic leukemia. Among patients with MDS, detection of mutations in SF3B1 define a subgroup of patients with the ring sideroblast form of MDS and a favorable prognosis. For patients with MPNs, detection of the BCR-ABL1 fusion delineates chronic myeloid leukemia from classic BCR-ABL1− MPNs, which are largely defined by mutations in JAK2, CALR, or MPL. In the B-cell lymphomas, detection of characteristic rearrangements involving MYC in Burkitt lymphoma, BCL2 in follicular lymphoma, and MYC/BCL2/BCL6 in high-grade B-cell lymphomas are essential for diagnosis. In T-cell lymphomas, anaplastic large-cell lymphoma is defined by mutually exclusive rearrangements of ALK, DUSP22/IRF4, and TP63. Genetic alterations affecting TP53 and the mutational status of the immunoglobulin heavy-chain variable region are important in clinical management of chronic lymphocytic leukemia. Additionally, detection of BRAFV600E mutations is helpful in the diagnosis of classical hairy cell leukemia and a number of histiocytic neoplasms. Numerous additional examples provided here demonstrate how clinical evaluation of genomic alterations have refined classification of myeloid neoplasms and major forms of lymphomas arising from B, T, or natural killer cells.

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Mutations in the JAK/STAT and RAS signaling pathways are common in intestinal T-cell lymphomas

Cited by 79 publications

References 14 publications

JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL

JAK/STAT-Activating Genomic Alterations Are a Hallmark of T-PLL

T- and NK-cell lymphoproliferative disorders of the gastrointestinal tract: review and update

Diagnosis and classification of hematologic malignancies on the basis of genetics

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