STAT5BN642H is a driver mutation for T cell neoplasia

Phạm, Hà; Maurer, Barbara; Prchal-Murphy, Michaela; Grausenburger, Reinhard; Grundschober, Eva; Javaheri, Tahereh; Nivarthi, Harini; Boersma, Auke; Kolbe, Thomas; Elabd, M; Halbritter, Florian; Pěnčík, Jan; Kazemi, Zahra; Grebien, Florian; Hengstschläger, Markus; Kenner, Lukas; Kubicek, Stefan; Farlik, Matthias; Bock, Christoph; Valent, Peter; Müller, Mathias; Rülicke, Thomas; Sexl, Veronika; Moriggl, Richard

doi:10.1172/jci94509

Cited by 70 publications

(123 citation statements)

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“…Several points should be made in terms of the STAT5b mutations. STAT5b N642H has been indeed identified as an oncogenic driver in innate-like lymphocytes (48), and a mouse model expressing human N642H mutated STAT5b has been described to develop severe CD8+ T cell neoplasia (49). Provided that IL-15 is an upstream factor of STAT5b and that IL-15 transgenic mice develops the aggressive variant of T or NK cell leukemia (50), the IL-15-STAT5 axis might be considered crucial for neoplastic transformation.…”

Section: Stat Mutation: Founding or Late Event?mentioning

confidence: 99%

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

et al. 2020

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Large granular lymphocyte leukemia (LGLL) is a chronic proliferation of clonal cytotoxic lymphocytes, usually presenting with cytopenias and yet lacking a specific therapy. The disease is heterogeneous, including different subsets of patients distinguished by LGL immunophenotype (CD8+ Tαβ, CD4+ Tαβ, Tγδ, NK) and the clinical course of the disease (indolent/symptomatic/aggressive). Even if the etiology of LGLL remains elusive, evidence is accumulating on the genetic landscape driving and/or sustaining chronic LGL proliferations. The most common gain-of-function mutations identified in LGLL patients are on STAT3 and STAT5b genes, which have been recently recognized as clonal markers and were included in the 2017 WHO classification of the disease. A significant correlation between STAT3 mutations and symptomatic disease has been highlighted. At variance, STAT5b mutations could have a different clinical impact based on the immunophenotype of the mutated clone. In fact, they are regarded as the signature of an aggressive clinical course with a poor prognosis in CD8+ T-LGLL and aggressive NK cell leukemia, while they are devoid of negative prognostic significance in CD4+ T-LGLL and Tγδ LGLL. Knowing the specific distribution of STAT mutations helps identify the discrete mechanisms sustaining LGL proliferations in the corresponding disease subsets. Some patients equipped with wild type STAT genes are characterized by less frequent mutations in different genes, suggesting that other pathogenetic mechanisms are likely to be involved. In this review, we discuss how the LGLL mutational pattern allows a more precise and detailed tumor stratification, suggesting new parameters for better management of the disease and hopefully paving the way for a targeted clinical approach.

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Section: Stat Mutation: Founding or Late Event?mentioning

confidence: 99%

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

et al. 2020

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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%

“…In humans, STAT5 -associated loss of function mutations are predominantly restricted to STAT5B and these culminate in growth failure, due to impaired growth hormone receptor signaling, as well as immunodeficiency, metabolic dysregulation and autoimmune disorders as a result of Treg deficiency (Cohen et al, 2006; Hwa, 2016; Kanai et al, 2012). In contrast, STAT5B gain of function (GOF) mutations strongly correlate with mature T cell neoplasms (Pham et al, 2018) and have also been found in patients with neutrophilia or eosinophilia (Cross et al, 2019; Ma et al, 2017). In particular, the recurrent N642H GOF missense mutation within the Src homology 2 (SH2) domain of STAT5B results in enhanced and prolonged tyrosine phosphorylation (pY) in response to low doses of cytokines or growth factors, and is associated with poorer patient prognosis and increased risk of relapse (Bandapalli et al, 2014; Pham et al, 2018; Rajala et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, STAT5B gain of function (GOF) mutations strongly correlate with mature T cell neoplasms (Pham et al, 2018) and have also been found in patients with neutrophilia or eosinophilia (Cross et al, 2019; Ma et al, 2017). In particular, the recurrent N642H GOF missense mutation within the Src homology 2 (SH2) domain of STAT5B results in enhanced and prolonged tyrosine phosphorylation (pY) in response to low doses of cytokines or growth factors, and is associated with poorer patient prognosis and increased risk of relapse (Bandapalli et al, 2014; Pham et al, 2018; Rajala et al, 2013). Interestingly, STAT5B GOF mutations are relatively frequent in aggressive γδ T cell lymphoma subtypes, such as hepatosplenic T cell lymphoma (Nicolae et al, 2014), monomorphic epitheliotropic intestinal T cell lymphoma (Kucuk et al, 2015; Nairismagi et al, 2016) and primary cutaneous γδ T cell lymphoma (Kucuk et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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

Kadekar

Agerholm

Rizk

et al. 2019

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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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Inhibitors Targeting STAT5 Signaling in Myeloid Leukemias: New Tetrahydroquinoline Derivatives with Improved Antileukemic Potential

et al. 2021

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Signal transducers and activators of transcription 5A and 5B (STAT5A and STAT5B) are two closely related STAT family members that are crucial downstream effectors of tyrosine kinase oncoproteins such as FLT3‐ITD in acute myeloid leukemia (AML) and BCR‐ABL in chronic myeloid leukemia (CML). We recently developed and reported the synthesis of a first molecule called 17 f that selectively inhibits STAT5 signaling in myeloid leukemia cells and overcomes their resistance to chemotherapeutic agents. To improve the antileukemic effect of 17 f, we synthesized ten analogs of this molecule and analyzed their impact on cell growth, survival, chemoresistance and STAT5 signaling. Two compounds, 7 a and 7 a’, were identified as having similar or higher antileukemic effects in various AML and CML cell lines. Both molecules were found to be more effective than 17 f at inhibiting STAT5 activity/expression and suppressing the chemoresistance of CML.

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STAT5BN642H is a driver mutation for T cell neoplasia

Cited by 70 publications

References 91 publications

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

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

Inhibitors Targeting STAT5 Signaling in Myeloid Leukemias: New Tetrahydroquinoline Derivatives with Improved Antileukemic Potential

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STAT5BN642H is a driver mutation for T cell neoplasia

Cited by 70 publications

References 91 publications

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

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

Inhibitors Targeting STAT5 Signaling in Myeloid Leukemias: New Tetrahydroquinoline Derivatives with Improved Antileukemic Potential

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