STAT1 activation in association with JAK2 exon 12 mutations

Godfrey, Anna L.; Chen, Edwin; Massie, Charles E.; Silber, Yvonne; Pagano, Francesca; Bellosillo, Beatríz; Guglielmelli, Paola; Harrison, Claire; Reilly, John T.; Stegelmann, Frank; Bijou, Fontanet; Lippert, Éric; Boiron, Jean Michel; Döhner, Konstanze; Vannucchi, Alessandro M.; Besses, Carlos; Green, Anthony

doi:10.3324/haematol.2015.128546

Cited by 11 publications

(11 citation statements)

References 29 publications

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“…18,19 Our data are in line with the recent results showing increased Stat1 activity in PV patients with JAK2 exon 12 mutations, similar to ET patients with JAK2-V617F. 11 To clarify the role of Stat1 in Jak2-Ex12 signaling, we analyzed Ex12;Stat1 2/2 double-mutant mice and found that loss of Stat1 had no effects on blood counts or the composition of BM and spleen progenitor cells ( Figure 6G-H), indicating that Stat1 does not play a central role in mediating the effects of Ex12 signaling on megakaryopoiesis or erythropoiesis. Finally, phosphorylation of Stat5 was not significantly increased compared with WT controls ( Figure 6B), whereas Jak2-V617F significantly increased both pStat3 and pStat5 ( Figure 6B-C).…”

Section: Discussionsupporting

confidence: 88%

“…5 Recently, the transcriptional profiles of erythroid colonies from PV patients with JAK2 exon 12 mutations were examined and a Stat1 signature was found. 11 To study the biology of PV caused by a JAK2 exon 12 mutation in more detail, we generated an inducible transgenic mouse model using a bacterial artificial chromosome (BAC) carrying the human JAK2 gene. For the transgene construct, we selected the JAK2-N542-E543del mutation because it is the most frequent subtype, occurring in ;30% of PV patients with a JAK2 exon 12 mutation.…”

Section: Introductionmentioning

confidence: 99%

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JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis

Grisouard

Kubovčáková

et al. 2016

Blood

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Key Points• Mice expressing a JAK2 exon 12 mutation display isolated erythrocytosis similar to the majority of patients with JAK2 exon 12 mutations.• JAK2 exon 12 mutation induces changes in iron metabolism that increase iron availability to allow maximal production of red cells.Mutations in JAK2 exon 12 are frequently found in patients with polycythemia vera (PV) that do not carry a JAK2-V617F mutation. The majority of these patients display isolated erythrocytosis. We generated a mouse model that expresses JAK2-N542-E543del, the most frequent JAK2 exon 12 mutation found in PV patients. Mice expressing the human JAK2-N542-E543del (Ex12) showed a strong increase in red blood cell parameters but normal neutrophil and platelet counts, and reduced overall survival. Erythropoiesis was increased in the bone marrow and spleen, with normal megakaryopoiesis and absence of myelofibrosis in histopathology. Erythroid progenitors and precursors were increased in hematopoietic tissues, but the numbers of megakaryocytic precursors were unchanged. Phosphorylation Stat3 and Erk1/2 proteins were increased, and a trend toward increased phospho-Stat5 and phospho-Stat1 was noted. However, Stat1 knock out in Ex12 mice induced no changes in platelet or red cell parameters, indicating that Stat1 does not play a central role in mediating the effects of Ex12 signaling on megakaryopoiesis or erythropoiesis. Ex12 mice showed decreased expression of hepcidin and increased expression of transferrin receptor-1 and erythroferrone, suggesting that the strong erythroid phenotype in Ex12 mutant mice is favored by changes in iron metabolism that optimize iron availability to allow maximal production of red cells. (Blood. 2016;128(6):839-851)

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis

Grisouard

Kubovčáková

et al. 2016

Blood

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“…Surprisingly, in a v-abl-driven model of STAT1 −/− leukemic cells initially harboring low MHC class I, enhanced MHC class I expression was gained during the disease progression, thereby reducing tumor recognition by NK cells [6]. As an exception, STAT1 was shown to be an oncogenic driver in T-cell acute lymphoblastic leukemia (T-ALL) and ALK + anaplastic large cell lymphoma (ALCL), and STAT1 is associated with the JAK2 exon 12 mutation in the progression of myeloproliferative neoplasms (MPNs) [7][8][9]. Reports on direct involvements of STAT2, STAT4 and STAT6 in cancerous processes are scarce and are not discussed here further [10].…”

Section: Introductionmentioning

confidence: 99%

Direct Targeting Options for STAT3 and STAT5 in Cancer

Orlova

Wagner

Araujo

et al. 2019

Cancers

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Signal transducer and activator of transcription (STAT)3 and STAT5 are important transcription factors that are able to mediate or even drive cancer progression through hyperactivation or gain-of-function mutations. Mutated STAT3 is mainly associated with large granular lymphocytic T-cell leukemia, whereas mutated STAT5B is associated with T-cell prolymphocytic leukemia, T-cell acute lymphoblastic leukemia and γδ T-cell-derived lymphomas. Hyperactive STAT3 and STAT5 are also implicated in various hematopoietic and solid malignancies, such as chronic and acute myeloid leukemia, melanoma or prostate cancer. Classical understanding of STAT functions is linked to their phosphorylated parallel dimer conformation, in which they induce gene transcription. However, the functions of STAT proteins are not limited to their phosphorylated dimerization form. In this review, we discuss the functions and the roles of unphosphorylated STAT3/5 in the context of chromatin remodeling, as well as the impact of STAT5 oligomerization on differential gene expression in hematopoietic neoplasms. The central involvement of STAT3/5 in cancer has made these molecules attractive targets for small-molecule drug development, but currently there are no direct STAT3/5 inhibitors of clinical grade available. We summarize the development of inhibitors against the SH2 domains of STAT3/5 and discuss their applicability as cancer therapeutics.

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“…JAK2 exon 12 mutations are tightly associated with PV in patients and mouse models (13). The reasons for these different abnormal phenotypic outcomes remain unclear and are likely to be complex (34,35).…”

Section: Introductionmentioning

confidence: 99%

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

et al. 2017

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Abstract. Myeloproliferative neoplasms (MPNs) result from the malignant transformation of a hematopoietic stem-cell (HSC), leading to abnormal amplification and proliferation of myeloid lineages. Identification of the Janus kinase 2 (JAK2) V617F mutation developed the knowledge of Philadelphia-negative (PN)-MPNs, contributing to and influencing the definition of the phenotype and prognostic impact. Considering the lack of Portuguese epidemiological data, the present study intends to characterize the prevalence of the JAK2 mutation in a PN-MPN versus a control Portuguese population. Caucasian Portuguese PN-MPN patients (n=133) and 281 matched control subjects were investigated. No significant differences were identified between the case and control groups concerning age distribution or smoking habits. Pathology distribution was as follows: 60.2% with essential thrombocythemia (ET), 29.3% with polycythemia vera (PV) and 10.5% with primary myelofibrosis (PMF). A total of 75.0% of patients were positive for the presence of the JAK2 V617F mutation. In addition, the prevalence of PV was 87.2%, ET was 73.4% and PMF was 50.0%. The JAK2 V617F mutation is observed in various MPN phenotypes, and has an increased incidence in ET patients and a decreased incidence in PV patients. These data may contribute to improving the knowledge of the pathophysiology of these disorders, and to a more rational and efficient selection of therapeutic strategies to be adopted, notably because most of the patients are JAK2 V617F negative.

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STAT1 activation in association with JAK2 exon 12 mutations

Cited by 11 publications

References 29 publications

JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis

JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis

Direct Targeting Options for STAT3 and STAT5 in Cancer

Prevalence of the Janus kinase 2 V617F mutation in Philadelphia-negative myeloproliferative neoplasms in a Portuguese population

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