High activation of STAT5A drives peripheral T-cell lymphoma and leukemia

Maurer, Barbara; Nivarthi, Harini; Wingelhofer, Bettina; Phạm, Hà; Schlederer, Michaela; Suske, Tobias; Grausenburger, Reinhard; Schiefer, Ana‐Iris; Prchal-Murphy, Michaela; Chen, Doris; Winkler, Susanne; Merkel, Olaf; Kornauth, Christoph; Hofbauer, Maximilian; Hochgatterer, Birgit; Hoermann, Gregor; Hoelbl-Kovacic, Andrea; Procházková, Jana; Lobello, Cosimo; Cumaraswamy, Abbarna A.; Latzka, Johanna; Kitzwögerer, Melitta; Chott, Andreas; Janíková, Andrea; Pospı́šilová, Šárka; Loizou, Joanna I.; Kubicek, Stefan; Valent, Peter; Kolbe, Thomas; Grebien, Florian; Kenner, Lukas; Gunning, Patrick T.; Královics, Róbert; Herling, Marco; Müller, Mathias; Rülicke, Thomas; Sexl, Veronika; Moriggl, Richard

doi:10.3324/haematol.2019.216986

Cited by 30 publications

(33 citation statements)

References 71 publications

(31 reference statements)

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“…Dysregulation of the JAK/STAT axis has been described as a key event in the pathogenesis of various hematologic malignancies [21]. Constitutively active JAK/STAT signaling induces T-cell tumors in mice [22,23]. Using different sequencing approaches, activating mutations of JAK1, JAK3, and STAT5B were identified as the most recurrent genomic aberrations affecting JAK/STAT genes in T-PLL [9][10][11][12][13][14][15][16][17][18].…”

Section: Introductionmentioning

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: Introductionmentioning

confidence: 99%

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

Wahnschaffe

Braun

Timonen

et al. 2019

Cancers

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“…Since deficiency in STAT5 resulted in near complete loss of γδT17 cells, we next examined the influence of hyperactive STAT5 expression. We utilized two established models of STAT5 hyperactivity whereby the Vav1 promoter drives the expression of (a) high or low copies of the hyperactive S710F STAT5A mutant (Maurer et al, 2019; Onishi et al, 1998), or (b) human wild-type (WT) or the hyperactive N642H STAT5B mutant (Pham et al, 2018). Constitutively high levels of hyperactive STAT5A resulted in very high numbers of γδT17 cells in LN, but hyperactivation of STAT5A had a considerably smaller impact on CD27 + γδ T cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Intestinal tissue from IL12 −/− mice (JAX stock #002692) was provided by Professor William W. Agace, (Lund University, Sweden). GOF STAT5a and STAT5b mice were generated as previously described (Maurer et al, 2019; Pham et al, 2018) and were bred at the University of Veterinary Medicine Vienna (Vienna, Austria). Frozen sperm samples from Tbet-AmCyan mice (Yu et al, 2015) were provided by Professor Jinfang Zhu (NIH/NIAID, MD) and after re-derivation mice bred in house.…”

Section: Methodsmentioning

confidence: 99%

The neonatal microenvironment programs conventional and intestinal Tbet⁺γδT17 cells through the transcription factor STAT5

Kadekar

Agerholm

Rizk

et al. 2019

Preprint

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15Interleukin(IL)-17-producing RORγt + γδ T (γδT17) cells develop in the embryonic thymus and 16 participate in type 3 immune responses. Herein we show that γδT17 cells rapidly proliferate within 17 neonatal lymph nodes and gut, where upon entry they uniquely upregulate Tbet and co-express IL-18 17, IL-22 and interferon(IFN) γ in a STAT3 and retinoic acid dependent manner. Neonatal 19 expansion was halted in mice conditionally deficient in STAT5 and its loss resulted in γδT17 cell 20 depletion from all adult organs. Hyperactive STAT5 mutant mice showed that the STAT5A 21 homologue had a dominant role over STAT5B in promoting γδT17 cell expansion and 22 downregulating gut-associated Tbet. In contrast, STAT5B preferentially expanded IFNγ-producing 23 γδ populations. Importantly, mice lacking γδT17 cells due to STAT5 deficiency displayed a 24 profound resistance to experimental autoimmune encephalomyelitis. Our data identify for the first 25 time STAT5 as a key molecular checkpoint allowing γδT17 cells to pass through a critical neonatal 26 developmental window to acquire tissue-specific characteristics essential for infection and 27 autoimmunity.28 subtypes, such as hepatosplenic T cell lymphoma (Nicolae et al., 2014), monomorphic 81 epitheliotropic intestinal T cell lymphoma (Kucuk et al., 2015; Nairismagi et al., 2016) and primary 82 cutaneous γδ T cell lymphoma (Kucuk et al., 2015). Notably, approximately 20% of identified 83 N642H mutations occur in γδ T cell derived lymphomas (de Araujo ED, 2019).84 4Herein, we show that STAT5 is critically required for the progression and expansion of γδT17 85 cells through neonatal life in the intestine and periphery. We provide evidence that intestinal γδT17 86 cells upregulate Tbet upon entry into the lamina propria after birth and co-express the cytokines IL-87 17, IL-22 and IFNγ in a mechanism dependent on STAT3 and retinoic acid. Furthermore, loss of 88 γδT17 cells due to STAT5 deficiency results in resistance to experimental autoimmune 89 encephalomyelitis in adult mice. Importantly, we show that STAT5A promotes γδT17 cell 90 expansion and downregulates intestinal Tbet favoring a type 17 program, whereas STAT5B favors 91 IFNγ-producing γδ populations and increases intestinal Tbet expression. Collectively, our data 92 suggest that neonatal life is a critical window of development and tissue specification for γδT17 93 cells, and that this process is tightly regulated by STAT5. 94 95 Results 96 STAT5 regulates the neonatal expansion of γδT17 cells 97 In order to test the importance of STAT5 in RORγt expressing γδ T cells, we crossed RORγt-Cre 98 mice (Eberl and Littman, 2004) with mice floxed for both STAT5a and STAT5b (RORγt CRE -99

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“…Accordingly, Kaech's group also reported that STAT5ca promoted memory CD8 T cells [49] that did not display any sign of transformation. However, Moriggl and colleagues recently demonstrated that high expression of S710F gain-of-function mutated STAT5A induced PTLC-nos (Peripheral T cell leukemia and lymphoma-not otherwise specified) cells when expressed during T cell development in transgenic mice [84].…”

Section: Role Of Stat5 In the Generation Of Memory Cd8 T Cells And Mamentioning

confidence: 99%

Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

Verdeil

Lawrence

Schmitt-Verhulst

et al. 2019

Cancers

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Oncogene-induced STAT3-activation is central to tumor progression by promoting cancer cell expression of pro-angiogenic and immunosuppressive factors. STAT3 is also activated in infiltrating immune cells including tumor-associated macrophages (TAM) amplifying immune suppression. Consequently, STAT3 is considered as a target for cancer therapy. However, its interplay with other STAT-family members or transcription factors such as NF-κB has to be considered in light of their concerted regulation of immune-related genes. Here, we discuss new attempts at re-educating immune suppressive tumor-associated macrophages towards a CD8 T cell supporting profile, with an emphasis on the role of STAT transcription factors on TAM functional programs. Recent clinical trials using JAK/STAT inhibitors highlighted the negative effects of these molecules on the maintenance and function of effector/memory T cells. Concerted regulation of STAT3 and STAT5 activation in CD8 T effector and memory cells has been shown to impact their tumor-specific responses including intra-tumor accumulation, long-term survival, cytotoxic activity and resistance toward tumor-derived immune suppression. Interestingly, as an escape mechanism, melanoma cells were reported to impede STAT5 nuclear translocation in both CD8 T cells and NK cells. Ours and others results will be discussed in the perspective of new developments in engineered T cell-based adoptive therapies to treat cancer patients. function of tumor-associated macrophages (TAM) and (ii) for the regulation of T cell functions. As STAT TFs are key players in the regulation of functions of these immune cells, their manipulation can have a beneficial or detrimental effect on the anti-tumor response depending on the targeted cell type. Tumor-Induced Inflammation Drives Accumulation of Tumor-Infiltrating Myeloid CellsCytokine receptor-induced signaling sustains and amplifies the activation of STAT3, NF-κB and AP-1 in a positive amplification loop, fueling tumor-associated inflammation. As such, a core inflammation-related gene set regulated by STAT3, NF-κB and AP-1 has recently been proposed as an "inflammatory index" in breast cancer cell lines and patient samples [4]. Importantly, in correlation with this inflammatory index, this study reported a concerted regulation of (i) non-inflammatory genes related to angiogenesis, metastasis, and cell proliferation; (ii) tumor genome instability; and (iii) heterogeneity of the tumor microenvironment (TME), including the recruited immune cells. Remarkably, these co-regulated characteristics were found across several cancer types driven by distinct oncogenes [4].Tumor-derived cytokines have been linked to the accumulation of immune-suppressive myeloid cells including both myeloid-derived suppressor cells (MDSCs; IMCs) and tumor-associated macrophages (TAM). In both human and mouse melanomas, IMCs have an important role in malignant progression and evasion from anti-tumor immunity that is linked to the suppression of T cell responses [6][7][8][9]. While increased...

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High activation of STAT5A drives peripheral T-cell lymphoma and leukemia

Abstract: 187Main Text: 3963

Cited by 30 publications

References 71 publications

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

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

The neonatal microenvironment programs conventional and intestinal Tbet⁺γδT17 cells through the transcription factor STAT5

Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

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High activation of STAT5A drives peripheral T-cell lymphoma and leukemia

Abstract: 187Main Text: 3963

Cited by 30 publications

References 71 publications

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

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

The neonatal microenvironment programs conventional and intestinal Tbet+γδT17 cells through the transcription factor STAT5

Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

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The neonatal microenvironment programs conventional and intestinal Tbet⁺γδT17 cells through the transcription factor STAT5