Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma

Song, Tongxing; Nairismägi, Maarja Liisa; Laurensia, Yurike; Lim, Jing Quan; Tan, Jian; Li, Zhi Mei; Pang, Wan Lu; Kizhakeyil, Atish; Wijaya, Giovani Claresta; Huang, Dachuan; Nagarajan, Sanjanaa; Chia, Burton K.; Cheah, Daryl Ming Zhe; Liu, Yan Hui; Zhang, Fen; Rao, Hui Lan; Tang, Tiffany; Wong, Esther Kam Yin; Bei, Jin Xin; Iqbal, Jabed; Grigoropoulos, Nicholas F.; Ng, Siok Bian; Chng, Wee Joo; Teh, Bin Tean; Tan, Soo Yong; Verma, Navin Kumar; Fan, Hao; Lim, Soon Thye; Ong, Choon Kiat

doi:10.1182/blood-2018-01-829424

Cited by 228 publications

(134 citation statements)

References 82 publications

(89 reference statements)

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“…The mutation has been observed previously in AITL, but also in adult T-cell lymphoma [10,35]. The STAT3 mutation P715L observed in two ALK − ALCLs and one PTCL-NOS case has been observed in NKTL previously [36].…”

Section: Discussionmentioning

confidence: 55%

STAT3 Mutation Is Associated with STAT3 Activation in CD30+ ALK− ALCL

Andersson

Brück

Braun

et al. 2020

Cancers

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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.Cancers 2020, 12, 702 2 of 17 diagnoses [1]. The most prevalent PTLCs are PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic lymphoma kinase-negative (ALK − ALCL), and anaplastic lymphoma kinase-positive anaplastic large cell lymphoma (ALK + ALCL) [2,3].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.Recent advances in the molecular and genetic characterization of PTCL have helped to delineate differences and similarities between the various subtypes [6]. Several recurrent mutations have been identified in small subsets of patients potentially enabling more accurate disease classification and guide treatment decisions. In AITL, the three most commonly identified genetic lesions occur in the Tet methylcytosine dioxygenase 2 gene (TET2), the Ras homolog gene family, member A (RHOA), and the isocitrate dehydrogenase 2 gene (IDH2). Besides AITL, TET2 mutations can be seen with a high frequency also in PTCL-NOS with a T follicular helper cell phenotype [7]. RHOA, a small GTPase participating i...

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Section: Discussionmentioning

confidence: 55%

STAT3 Mutation Is Associated with STAT3 Activation in CD30+ ALK− ALCL

Andersson

Brück

Braun

et al. 2020

Cancers

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“…Abnormal activation of the JAK/STAT pathway, which can be assessed by STAT3 and STAT5 phosphorylation, is pervasive in diverse T-cell malignancies [121]. In peripheral T-cell lymphoma (PTCL) and extranodal NKTCL, recurrent mutations in STAT3 are most frequent, followed by JAK1, JAK3, and SOCS1 (Table 1) [44]. STAT3 mutations are activated and lead to increased phosphorylation and transcriptional activity of STAT3 [25].…”

Section: T-cell Lymphomasmentioning

confidence: 99%

“…STAT3 mutations are activated and lead to increased phosphorylation and transcriptional activity of STAT3 [25]. In addition to promoting cell survival and proliferation, constitutive activation of STAT3 in cancer cells causes high levels of PD-L1 expression, which may facilitate tumor immune evasion (Figure 3) [44]. Activating STAT3 mutations are present in 50% of NK cell lines and 67% of γδ-T-cell lines (67%) but only in 5.9% of NKTCL and 8.3% of γδ-PTCL patient samples [43].…”

Section: T-cell Lymphomasmentioning

confidence: 99%

“…Constitutive activation of STAT3 and STAT5, which can be driven by the common gamma chain (γc) receptor-dependent cytokines IL-2, -4, -7, -9, -15, and -21, is pervasive in diverse T-cell malignancies [121]. In PTCL and NKTCL, activating mutations in STAT3, JAK1, and JAK3, and loss of function mutations in SOCS-1 and p53 enhance oncogenic effects of STAT3 and STAT5 by promoting cancer cell survival, modulating the tumor microenvironment and facilitating tumor immune evasion [44]. Constitutive activation of STAT3 and STAT5, which can be driven by the common gamma chain (γc) receptor-dependent cytokines IL-2, -4, -7, -9, -15, and -21, is pervasive in diverse T-cell malignancies [121].…”

Section: T-cell Lymphomasmentioning

confidence: 99%

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STAT3 Activation and Oncogenesis in Lymphoma

Zhu

Wang²,

2019

Cancers

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Signal transducer and activator of transcription 3 (STAT3) is an important and the most studied transcription factor in the Janus kinase (JAK)/STAT signaling pathway. STAT3 mediates the expression of various genes that play a critical role in many cellular and biological processes, such as cell proliferation, survival, differentiation, migration, angiogenesis, and inflammation. STAT3 and associated JAKs are activated and tightly regulated by a variety of cytokines and growth factors and their receptors in normal immune responses. However, abnormal expression of STAT3 leads to its constitutive activation, which promotes malignant transformation and tumor progression through oncogenic gene expression in numerous human cancers. Human lymphoma is a heterogeneous malignancy of T and B lymphocytes. Constitutive signaling by STAT3 is an oncogenic driver in several types of B-cell lymphoma and most of T-cell lymphomas. Aberrant STAT3 activation can also induce inappropriate expression of genes involved in tumor immune evasion such as PD-L1. In this review, we focus on the oncogenic role of STAT3 in human lymphoma and highlight potential therapeutic intervention by targeting JAK/STAT3 signaling.

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“…It was of peculiar interest to us that the two GNAQ hotspot somatic mutations (p.T96S and p.Y101X) reported in this study were never reported in other NKTCL studies that used NGS too [3][4][5][6] . We analyzed the Sanger sequences provided in Supplementary Fig.…”

Section: Recurrent Pt96s and Py101x Somatic Mutations Are Potentialmentioning

confidence: 59%

Correspondence: Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma

Lim

Ong

2020

Preprint

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Recurrent GNAQ mutation encoding p.T96S in natural-killer/T cell lymphoma (NKTCL) was recently reported in 8.7% (11/127) of NKTCL patients. At the time of publication, this phenomenon was not observed in preceding genomic studies of NKTCL. We suspected that p.T96S was a false-positive somatic call due to misaligned sequencing reads that originated from the highly similar GNAQpseudogene (GNAQP) chr2q21.1 locus. Linkage disequilibrium analysis also revealed that GNAQP has high frequencies of co-occurring polymorphic mismatches which led to the preferential misalignment of sequencing reads to the GNAQ chr9q21.2 locus instead. This correspondence implicates our interpretation of true-positive somatic variants and many other studies which could be affected by similar suboptimal interpretation of somatic mutations.

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Oncogenic activation of the STAT3 pathway drives PD-L1 expression in natural killer/T-cell lymphoma

Cited by 228 publications

References 82 publications

STAT3 Mutation Is Associated with STAT3 Activation in CD30+ ALK− ALCL

STAT3 Mutation Is Associated with STAT3 Activation in CD30+ ALK− ALCL

STAT3 Activation and Oncogenesis in Lymphoma

Correspondence: Recurrent GNAQ mutation encoding T96S in natural killer/T cell lymphoma

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