Abstract
Peripheral T-cell lymphomas (PTCL) are a heterogeneous, and often aggressive group of non-Hodgkin lymphomas. Recent advances in the molecular and genetic characterization of PTCLs have helped to delineate differences and similarities between the various subtypes, and the JAK/STAT pathway has been found to play an important oncogenic role. Here, we aimed to characterize the JAK/STAT pathway in PTCL subtypes and investigate whether the activation of the pathway correlates with the frequency of STAT gene mutations. Patient samples from AITL (n = 30), ALCL (n = 21) and PTCL-NOS (n = 12) cases were sequenced for STAT3, STAT5B, JAK1, JAK3, and RHOA mutations using amplicon sequencing and stained immunohistochemically for pSTAT3, pMAPK, and pAKT. We discovered STAT3 mutations in 13% of AITL, 13% of ALK+ ALCL, 38% of ALK− ALCL and 17% of PTCL-NOS cases. However, no STAT5B mutations were found and JAK mutations were only present in ALK- ALCL (15%). Concurrent mutations were found in all subgroups except ALK+ ALCL where STAT3 mutations were always seen alone. High pY-STAT3 expression was observed especially in AITL and ALCL samples. When studying JAK-STAT pathway mutations, pY-STAT3 expression was highest in PTCLs harboring either JAK1 or STAT3 mutations and CD30+ phenotype representing primarily ALK− ALCLs. Further investigation is needed to elucidate the molecular mechanisms of JAK-STAT pathway activation in PTCL.
Highlights
Peripheral T-cell lymphomas (PTCLs) form a heterogeneous, uncommon, and often aggressive group of non-Hodgkin’s lymphomas (NHL) representing approximately 10–15% of all new NHLCancers 2020, 12, 702; doi:10.3390/cancers12030702 www.mdpi.com/journal/cancersCancers 2020, 12, 702 diagnoses [1]
The entire STAT3 gene and the hotspot SH2-domain of STAT5B were screened by targeted amplicon sequencing in 63 patients with T-cell lymphoma
We discovered that 13% of angioimmunoblasticT-cell lymphoma (AITL) and ALK+ ALCL cases and 17% of PTCL-not otherwise specified (NOS) cases harbored STAT3 mutations
Summary
Peripheral T-cell lymphomas (PTCLs) form a heterogeneous, uncommon, and often aggressive group of non-Hodgkin’s lymphomas (NHL) representing approximately 10–15% of all new NHLCancers 2020, 12, 702; doi:10.3390/cancers12030702 www.mdpi.com/journal/cancersCancers 2020, 12, 702 diagnoses [1]. Despite generally favorable response rates to chemotherapy, remissions are often not durable, and as such the natural history of PTCL is characterized by relapses and refractory disease. For this reason, upfront hematopoietic stem cell transplantation (HSCT) is often recommended in first remission for patients who are fit and have chemo-sensitive disease [4]. For patients who are not suitable for transplantation, chances of long-term disease control are very limited, with an average progression-free survival (PFS) of 5.5 months [5] In this setting, optimal therapeutic approaches remain undefined representing an unmet clinical need
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