Genetic Knock-out of TNFR1 and TNFR2 in a JAK2-V617F Polycythemia Vera Mouse Model.
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SUBMITTER: Muller P
PROVIDER: S-EPMC9015207 | biostudies-literature | 2022 May
REPOSITORIES: biostudies-literature
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Genetic Knock-out of TNFR1 and TNFR2 in a JAK2-V617F Polycythemia Vera Mouse Model.
Müller Peter P Baldauf Conny K CK Haage Tobias R TR Charakopoulos Emmanouil E Böttcher Martin M Bhuria Vikas V Mougiakakos Dimitrios D Schraven Burkhart B Fischer Thomas T
HemaSphere 20220415 5
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Project description:Chronic nonresolving inflammatory syndrome is a major disease feature in myeloproliferative neoplasms (MPNs). Systemic inflammation promotes the growth of the JAK2-V617F+ hematopoietic stem cell clone and is associated with constitutive symptoms (eg, fever, cachexia, and fatigue). Therefore, it is being discussed whether anti-inflammatory therapy, in addition to the well-established JAK inhibitor therapy, may be beneficial in the control of constitutive symptoms. Moreover, effective control of the inflammatory microenvironment may contribute to prevent transformation into secondary myelofibrosis and acute leukemia. Given the pivotal role of tumor necrosis factor α (TNF-α) in MPN and the distinct roles of TNF-α receptor 1 (TNFR1) and TNFR2 in inflammation, we investigated the therapeutic effects of αTNFR1 and αTNFR2 antibody treatment in MPN-like disease using the JAK2+/VF knock-in mouse model. Peripheral blood counts, bone marrow/spleen histopathology, and inflammatory cytokine levels in serum were investigated. αTNFR2 antibody treatment decreased white blood cells and modulated the serum levels of several cytokines [CXCL2, CXCL5, interleukin-12(p40)], as well as of macrophage colony-stimulating factor, but they lacked efficacy to ameliorate hematocrit and splenomegaly. αTNFR1 antibody treatment resulted in the mild suppression of elevated hematocrit of -10.7% and attenuated splenomegaly (22% reduction in spleen weight). In conclusion, our studies show that TNFR1 and TNFR2 play different roles in the biology of JAK2-V617F-induced disease that may be of relevance in future therapeutic settings.
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Project description:Although a large proportion of patients with polycythemia vera (PV) harbor a valine-to-phenylalanine mutation at amino acid 617 (V617F) in the JAK2 signaling molecule, the stage of hematopoiesis at which the mutation arises is unknown. Here we isolated and characterized hematopoietic stem cells (HSC) and myeloid progenitors from 16 PV patient samples and 14 normal individuals, testing whether the JAK2 mutation could be found at the level of stem or progenitor cells and whether the JAK2 V617F-positive cells had altered differentiation potential. In all PV samples analyzed, there were increased numbers of cells with a HSC phenotype (CD34+CD38-CD90+Lin-) compared with normal samples. Hematopoietic progenitor assays demonstrated that the differentiation potential of PV was already skewed toward the erythroid lineage at the HSC level. The JAK2 V617F mutation was detectable within HSC and their progeny in PV. Moreover, the aberrant erythroid potential of PV HSC was potently inhibited with a JAK2 inhibitor, AG490.
| S-EPMC1434515 | biostudies-literature
Project description:Polycythemia vera (PV) is a chronic myeloproliferative neoplasm that is associated with a substantial symptom burden, thrombohemorrhagic complications, and impaired survival. A decade after the seminal discovery of an activating mutation in the tyrosine kinase JAK2 in nearly all patients with PV, new treatment options are finally beginning to emerge, necessitating a critical reappraisal of the underlying pathogenesis and therapeutic modalities available for PV. Herein, we comprehensively review clinical aspects of PV including diagnostic considerations, natural history, and risk factors for thrombosis. We summarize recent studies delineating the genetic basis of PV, including their implications for evolution to myelofibrosis and secondary acute myeloid leukemia. We assess the quality of evidence to support the use of currently available therapies, including aspirin, phlebotomy, hydroxyurea, and interferon. We analyze recent studies evaluating the safety and efficacy of JAK inhibitors, such as ruxolitinib, and evaluate their role in the context of other available therapies for PV. This review provides a framework for practicing hematologists and oncologists to make rational treatment decisions for patients with PV.
| S-EPMC4979103 | biostudies-literature
Project description:BackgroundAlthough reduction in the JAK2(V617F) allele burden (%V617F) has been suggested as a criterion for defining disease response to cytoreductive therapy in polycythemia vera, its value as a response monitor is unclear. The purpose of this study is to determine whether a reduction in %V617F in polycythemia vera is a prerequisite to achieving hematologic remission in response to cytoreductive therapy.Design and methodsWe compared the clinical and hematologic responses to change in %V617F (molecular response) in 73 patients with polycythemia vera treated with either interferon (rIFN?-2b: 28, Peg-rIFN?-2a: 18) or non-interferon drugs (n=27), which included hydroxyurea (n=8), imatinib (n=12), dasatinib (n=5), busulfan (n=1), and radioactive phosphorus (n=1). Hematologic response evaluation employed Polycythemia Vera Study Group criteria, and molecular response evaluation, European Leukemia Net criteria.ResultsOf the 46 treated with interferon, 41 (89.1%) had a hematologic response, whereas only 7 (15.2%) had a partial molecular response. Of the 27 who received non-interferon treatments, 16 (59.3%) had a hematologic response, but only 2 (7.4%) had a molecular response. Median duration of follow up was 2.8 years. Statistical agreement between hematologic response and molecular response was poor in all treatment groups.ConclusionsGenerally, hematologic response was not accompanied by molecular response. Therefore, a quantitative change in %V617F is not required for clinical response in patients with polycythemia vera.
| S-EPMC3347655 | biostudies-literature
Project description:The JAK2 V617F mutation is found in most patients with a myeloproliferative neoplasm and is sufficient to produce a myeloproliferative phenotype in murine retroviral transplantation or transgenic models. However, several lines of evidence suggest that disease phenotype is influenced by the level of mutant JAK2 signaling, and we have therefore generated a conditional knock-in mouse in which a human JAK2 V617F is expressed under the control of the mouse Jak2 locus. Human and murine Jak2 transcripts are expressed at similar levels, and mice develop modest increases in hemoglobin and platelet levels reminiscent of human JAK2 V617F-positive essential thrombocythemia. The phenotype is transplantable and accompanied by increased terminal erythroid and megakaryocyte differentiation together with increased numbers of clonogenic progenitors, including erythropoietin-independent erythroid colonies. Unexpectedly, JAK2(V617F) mice develop reduced numbers of lineage(-)Sca-1(+)c-Kit(+) cells, which exhibit increased DNA damage, reduced apoptosis, and reduced cell cycling. Moreover, competitive bone marrow transplantation studies demonstrated impaired hematopoietic stem cell function in JAK2(V617F) mice. These results suggest that the chronicity of human myeloproliferative neoplasms may reflect a balance between impaired hematopoietic stem cell function and the accumulation of additional mutations.
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| S-EPMC5566046 | biostudies-literature
Project description:BackgroundJAK2 V617F, a somatic point mutation that leads to constitutive JAK2 phosphorylation and kinase activation, has been incorporated into the WHO classification and diagnostic criteria of myeloid neoplasms. Although various approaches such as restriction fragment length polymorphism, amplification refractory mutation system and real-time PCR have been developed for its detection, a generic rapid closed-tube method, which can be utilized on routine genetic testing instruments with stability and cost-efficiency, has not been described.Methodology/principal findingsAsymmetric PCR for detection of JAK2 V617F with a 3'-blocked unlabeled probe, saturate dye and subsequent melting curve analysis was performed on a Rotor-Gene® Q real-time cycler to establish the methodology. We compared this method to the existing amplification refractory mutation systems and direct sequencing. Hereafter, the broad applicability of this unlabeled probe melting method was also validated on three diverse real-time systems (Roche LightCycler® 480, Applied Biosystems ABI® 7500 and Eppendorf Mastercycler® ep realplex) in two different laboratories. The unlabeled probe melting analysis could genotype JAK2 V617F mutation explicitly with a 3% mutation load detecting sensitivity. At level of 5% mutation load, the intra- and inter-assay CVs of probe-DNA heteroduplex (mutation/wild type) covered 3.14%/3.55% and 1.72%/1.29% respectively. The method could equally discriminate mutant from wild type samples on the other three real-time instruments.ConclusionsWith a high detecting sensitivity, unlabeled probe melting curve analysis is more applicable to disclose JAK2 V617F mutation than conventional methodologies. Verified with the favorable inter- and intra-assay reproducibility, unlabeled probe melting analysis provided a generic mutation detecting alternative for real-time instruments.
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