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Genetic analysis of myeloproliferative neoplasms

English title Genetic analysis of myeloproliferative neoplasms
Applicant Skoda Radek
Number 166613
Funding scheme Project funding (Div. I-III)
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Experimental Cancer Research
Start/End 01.06.2016 - 31.05.2019
Approved amount 756'000.00
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All Disciplines (3)

Discipline
Experimental Cancer Research
Genetics
Pathophysiology

Keywords (5)

chromosomal aberrations; transgenic mice; myeloproliferative disorders; Janus kinase; hematopoiesis

Lay Summary (German)

Lead
Unser Forschungsprojekt zielt darauf die Entstehung bestimmter Formen von chronischer Leukämie, genannt “myeloproliferative Neoplasmen (MPN), auf molekularer und genetischer Ebene zu verstehen um die Diagnose und Behandlung dieser Erkrankungen zu verbessern.
Lay summary

Unsere Forschungsgruppe hat im Jahr 2005 eine Mutation in der Januskinase 2 (JAK2) gefunden, einem Schlüsselprotein, das Wachstums-Signale im Zellinnern von Blutvorläuferzellen übermittelt. Das mutierte JAK2-V617F Protein ist hyperaktiv und ist ein wesentlicher Faktor, welcher die Überproduktion von Blutzellen bei der MPN Erkrankung antreibt. Wir haben Hinweise, dass dieses mutierte Protein den Stoffwechsel der Stammzellen stark verändert und wollen diese Veränderungen nutzen, um neue Angriffspunkte für Therapie zu finden. Inzwischen wurden auch Mutationen in anderen Genen gefunden, die bei MPN Patienten zusammen oder anstatt von JAK2-V617F auftreten können. Unser Projekt untersucht die Funktion und das Zusammenspiel zwischen JAK2-V617F und diesen neuen Mutationen bei der Entstehung von MPN. Dabei haben wir Veränderungen in der Expression von Zielproteinen gefunden, die als Konsequenz der Mutationen überexprimiert werden und so auch die Blutbildung steigern. Wir werden untersuchen, ob diese verstärkt exprimierten Zielproteine  beeinflusst werden können und so Angriffpunkte für neue therapeutische Interventionen darstellen.

 

Die zu erwartenden Erkenntnisse aus diesem Projekt werden unser Verständnis der  Entstehung der MPN Erkrankungen voran bringen und könnten auch die Behandlung von MPN Patienten verbessern, indem die Stammzellen, welche die Erkrankung aufrecht erhalten gezielter angegangen werden mit Kombinationen von Medikamenten, oder neu zu entwickelnde Therapieansätzen, die gezielter die malignen Stammzellen angreifen.

 

Direct link to Lay Summary Last update: 23.06.2016

Responsible applicant and co-applicants

Publications

Publication
The sympathomimetic agonist mirabegron did not lower JAK2-V617F allele burden, but restored nestin-positive cells and reduced reticulin fibrosis in patients with myeloproliferative neoplasms: results
DrexlerBeatrice, PasswegJakob R., TzankovAlexander, BiglerMartin, TheocharidesAlexandre PA, CantoniNathan, KellerPeter, StussiGeorg, RueferAxel, BenzRudolf, FavreGeneviève, LundbergPontus, NienholdRonny, FuhrerAndrea, BiaggiChristine, ManzMarkus G., BargetziMario, Mendez-FerrerSimon, SkodaRadek C. (2019), The sympathomimetic agonist mirabegron did not lower JAK2-V617F allele burden, but restored nestin-positive cells and reduced reticulin fibrosis in patients with myeloproliferative neoplasms: results, in Haematologica, 104(4), 710-716.
Dual roles of EZH2 in acute myeloid leukemia
SkodaRadek C., SchwallerJürg (2019), Dual roles of EZH2 in acute myeloid leukemia, in Journal of Experimental Medicine, 216(4), 725-727.
Accelerating myelofibrosis through loss of Dnmt3a
SkodaRadek C. (2018), Accelerating myelofibrosis through loss of Dnmt3a, in Blood, 132(26), 2703-2704.
A Gain-of-Function Mutation in EPO in Familial Erythrocytosis
ZmajkovicJakub, LundbergPontus, NienholdRonny, TorgersenMaria L., SundanAnders, WaageAnders, SkodaRadek C. (2018), A Gain-of-Function Mutation in EPO in Familial Erythrocytosis, in The New England Journal of Medicine, 378(10), 924-930.
Loss of Ezh2 synergizes with JAK2-V617F in initiating myeloproliferative neoplasms and promoting myelofibrosis
ShimizuTakafumi, KubovcakovaLucia, NienholdRonny, ZmajkovicJakub, MeyerSara C., Hao-ShenHui, GeierFlorian, DirnhoferStephan, GuglielmelliPaola, VannucchiAlessandro M., Milosevic FeenstraJelena D., KralovicsRobert, OrkinStuart H., SkodaRadek R. (2016), Loss of Ezh2 synergizes with JAK2-V617F in initiating myeloproliferative neoplasms and promoting myelofibrosis, in The Journal of Experimental Medicine, 213(8), 1479-1496.
JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis
GrisouardJean, LiSai, KubovcakovaLucia, Nageswara RaoTata, MeyerSara C., LundbergPontus, Hao-ShenHui, RomanetVincent, MurakamiMasato, RadimerskiThomas, DirnhoferStephan, SkodaRadek S. (2016), JAK2 exon 12 mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis, in Blood, 128(6), 839-851.
Homozygous calreticulin mutations in patients with myelofibrosis lead to acquired myeloperoxidase deficiency
TheocharidesAlexandre P.A., LundbergPontus, LakkarajuAsvin K.K., LysenkoVeronika, MyburghRenier, AguzziAdriano, SkodaRadek C., ManzMarkus G. (2016), Homozygous calreticulin mutations in patients with myelofibrosis lead to acquired myeloperoxidase deficiency, in Blood, 127(25), 3253-3259.
JAK2 mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms
Nageswara RaoTata, HansenNils, HilfikerJulian, RaiShivam, MajewskaJulia-Magdalena, LekovicDanijela, GezerDeniz, AndinaNicola, GalliSerena, CasselTeresa, GeierFlorian, DelezieJulien, NienholdRonny, Hao-ShenHui, BeiselChristian, Di PalmaSerena, DimeloeSarah, TrebickaJonel, WolfDiminik, GassmannMax, Fan Teresa W-M., LaneAndrew N., HandschinChristoph, DirnhoferStefan, KrögerNicolaus, HessChristoph, RadimerskiThomas, KoschmiederSteffen, CokicVladan P., SkodaRadek C., JAK2 mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms, in Blood, 31511238.

Collaboration

Group / person Country
Types of collaboration
Dr. Christian Beisel, D-BSSE, ETH Zürich Switzerland (Europe)
- Research Infrastructure
Prof. Stuart Orkin, Harvard Medical School, Boston, USA United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Christoph Handschin Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Prof. Vladan Cokic, University of Belgrade Serbien (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Stephan Dirnhofer, University Hospital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Prof. Jakob Passweg, Division of Hematology, University Hospital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Dr. Robert Kralovics, CeMM, Vienna Austria (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Markus Manz, University Hospital Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication

Associated projects

Number Title Start Funding scheme
185297 Genetic analysis of myeloproliferative neoplasms 01.06.2019 Project funding (Div. I-III)
152420 Determination of the mutational landscape and clonal architecture and its application in angiogenesis and thrombosis of MPN patients 01.04.2014 SCOPES
185297 Genetic analysis of myeloproliferative neoplasms 01.06.2019 Project funding (Div. I-III)
147016 Genetic analysis of myeloproliferative neoplasms 01.06.2013 Project funding (Div. I-III)

Abstract

2.1. SUMMARY OF THE RESEARCH PLAN (max. 1 page)Myeloproliferative neoplasms (MPN) are a group of diseases characterized by aberrant proliferation of the erythroid, megakaryocytic and myeloid lineages. They represent clonal disorders of the hematopoietic stem cell with an inherent tendency towards leukemic transformation. MPN are subdivided into three disease entities: polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). Somatic gain of function mutations in the genes JAK2, CALR, or MPL can be detected in blood cells of close to 90% of MPN patients. These gene mutations are known to act as drivers that can cause MPN phenotypes in patients and mouse models. MPN is a clonal disease of the hematopoietic stem cells. Disease manifestation and prognosis is in part influenced by additional somatic mutation that synergize with the driver mutations, but alone do not cause disease. These additional mutations most frequently occur in genes encoding epigenetic regulators, such as TET2, DNMT3a or EZH2. JAK2-V617F is the most frequent driver gene mutation occurring in 70-80% of MPN patients. Why some patients with JAK2-V617F, develop ET while others manifest as PV remains an open question. In contrast, JAK2 exon 12 mutations are tightly associated with PV and in many cases present as pure erythrocytosis. Both types of JAK2 mutations signal through the same C-terminal tyrosine kinase of JAK2, but result in very different phenotypic readouts. Furthermore, various knockin and transgenic mouse models of JAK2-V617F substantially differ in phenotypes, despite existing on the same genetically defined inbred background. We derived hypotheses and found factors that are likely to influence the phenotypic expression of MPN, which we will study in this proposal. We also derived preliminary data suggesting that the MPN hematopoietic stem cells are profoundly altered in their metabolism. Finally, we identified potential target genes that mediate the synergistic effects of JAK2-V617F and the loss of the epigenetic regulator EZH2. The proposed experiments will address the following specific aims:1. To examine genotype-phenotype correlations in MPN and define factors that determine ET versus PV phenotypes in MPN with mutated JAK2.2. To characterize altered characteristics of MPN stem cells, in particular the changes in transcriptome, metabolism, autophagy and lysosomal integrity.3. To study synergism between JAK2-V617F and mutations in epigenetic regulators in MPN pathogenesis and functionally test and validate candidate targets that mediate loss of Ezh2 in MPN.Significance: Our studies address important unsolved questions in the pathogenesis of MPN. We aim to test new hypotheses that may explain why one mutation (JAK2-V617F) can manifest as different clinical entities (ET or PV) with large inter-individual variation in the involvement of peripheral blood lineages. We also focus on poorly studied aspects of MPN stem cell biology, in particular metabolism, that could have major impact on the biology of MPN and may represent target for specific intervention. Our studies of synergism between JAK2-V617F and mutations in epigenetic regulator genes are likely to yield new insight into MPN progression to myelofibrosis and acute leukemia.
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