STAT5BN642H drives transformation of NKT cells: a novel mouse model for CD56+ T-LGL leukemia

Klein, Klara R.; Witalisz-Siepracka, Agnieszka; Maurer, Barbara; Prinz, Daniela; Heller, Gerwin; Leidenfrost, Nicoletta; Prchal-Murphy, Michaela; Suske, Tobias; Moriggl, Richard; Sexl, Veronika

doi:10.1038/s41375-019-0471-3

Cited by 13 publications

(16 citation statements)

References 12 publications

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“…In line, in a mouse B cell lymphoma model Ruxolitinib treatment promotes tumor progression by enhancing NK cell-derived VEGF-A expression (122). On the other hand, Ruxolitinib treatment significantly reduces disease burden in the context of CD56 + T-cell large granular lymphocytic (T-LGL) leukemia (170) and restores impaired NK cell functions in patients harboring STAT1 GOF mutations (96).…”

Section: Discussionmentioning

confidence: 99%

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JAK/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation

et al. 2019

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Natural Killer (NK) cells are cytotoxic lymphocytes of the innate immune system and play a critical role in anti-viral and anti-tumor responses. NK cells develop in the bone marrow from hematopoietic stem cells (HSCs) that differentiate through common lymphoid progenitors (CLPs) to NK lineage-restricted progenitors (NKPs). The orchestrated action of multiple cytokines is crucial for NK cell development and maturation. Many of these cytokines such as IL-2, IL-7, IL-12, IL-15, IL-21, IL-27, and interferons (IFNs) signal via the Janus Kinase / Signal Transducer and Activator of Transcription (JAK/STAT) pathway. We here review the current knowledge about these cytokines and the downstream signaling involved in the development and maturation of conventional NK cells and their close relatives, innate lymphoid cells type 1 (ILC1). We further discuss the role of suppressor of cytokine signaling (SOCS) proteins in NK cells and highlight their potential for therapeutic application.

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Section: Discussionmentioning

confidence: 99%

“…In line with observations in mice, patients with a STAT5B LOF mutation harbor significantly reduced NK cell numbers (166–168). STAT5 GOF mutations are found in malignancies of innate and innate-like lymphoid cells (125, 127, 169) and drive tumorigenesis in mouse NKT cells (170).…”

Section: Jak/stat Signalingmentioning

confidence: 99%

JAK/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation

et al. 2019

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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%

“…Depending on the immunophenotype of the mutated clone, the presence of STAT5b mutations in the same hotspot positions represents a signature of aggressive clinical course with a poor prognosis in aggressive CD8+ T-LGLL patients (28), while it is devoid of negative prognostic significance in CD4+ T-LGLL and Tγδ LGLL patients (15,29,53). The issue is quite intriguing since STAT5b N642H behaves as a driver mutation in several T-cell lymphomas and in the mice model it is enough to induce a leukemic phenotype (48).…”

Section: The Clinical Impact Of Stat3 and Stat5b Mutationsmentioning

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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“…Aberrant activation of JAK/STAT signaling is a hallmark of LGL leukemia. Increased activation of this pathway results from increased cytokine signaling [4,37] and somatic activating mutations in STAT3 [19,22,38] and STAT5B [19,20,39], further implicating the oncogenic role of this pathway in LGL leukemia. WGS on a small cohort of NK-LGL leukemia patients did not reveal mutations in JAK1 (manuscript under review).…”

Section: Discussionmentioning

confidence: 99%

Whole Genome Sequencing of Spontaneously Occurring Rat Natural Killer Large Granular Lymphocyte Leukemia Identifies JAK1 Somatic Activating Mutation

Wang

Yang

Dighe

et al. 2020

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Large granular lymphocyte (LGL) leukemia arises spontaneously in elderly Fischer (F344) rats. This rodent model has been shown to emulate many aspects of the natural killer (NK) variant of human LGL leukemia. Previous transplantation of leukemic material into young F344 rats resulted in several strains of rat NK (RNK) primary leukemic cells. One strain, RNK-16, was adapted into the RNK-16 cell line and established as an aggressive NK-LGL leukemia model. Whole genome sequencing of the RNK-16 cell line identified 255,838 locations where the RNK16 had an alternate allele that was different from F344, including a mutation in Jak1. Functional studies showed Jak1 Y1034C to be a somatic activating mutation that mediated increased STAT signaling, as assessed by phosphoprotein levels. Sanger sequencing of Jak1 in RNK-1, -3, -7, and -16 found only RNK-16 to harbor the Y1034C Jak1 mutation. In vivo studies revealed that rats engrafted with RNK-16 primary material developed leukemia more rapidly than those engrafted with RNK-1, -3, and -7. Additionally, ex vivo RNK-16 spleen cells from leukemic rats exhibited increased STAT1, STAT3, and STAT5 phosphorylation compared to other RNK strains. Therefore, we report and characterize a novel gain-of-function Jak1 mutation in a spontaneous LGL leukemia model that results in increased downstream STAT signaling.

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STAT5BN642H drives transformation of NKT cells: a novel mouse model for CD56+ T-LGL leukemia

Cited by 13 publications

References 12 publications

JAK/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation

JAK/STAT Cytokine Signaling at the Crossroad of NK Cell Development and Maturation

Insights Into Genetic Landscape of Large Granular Lymphocyte Leukemia

Whole Genome Sequencing of Spontaneously Occurring Rat Natural Killer Large Granular Lymphocyte Leukemia Identifies JAK1 Somatic Activating Mutation

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