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Genetic analysis of myeloproliferative neoplasms

English title Genetic analysis of myeloproliferative neoplasms
Applicant Skoda Radek
Number 147016
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 01.06.2013 - 31.05.2016
Approved amount 643'081.96
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All Disciplines (3)

Discipline
Experimental Cancer Research
Genetics
Pathophysiology

Keywords (5)

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

Lay Summary (German)

Lead
Genetic Analysis of Myeloproliferative DisordersProf. Dr. Radek Skoda, Department of Biomedicine, Experimental Hematology, University Hospital Basel
Lay summary

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.

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. 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. Insbesondere wollen wir die Bedeutung dieser Mutation für die MPN Stammzellen verstehen,  die für die Aufrechterhaltung der MPN Erkrankung verantwortlich sind. Zusätzlich versuchen wir, die Bedeutung dieser Mutation für den Verlauf der Erkrankung bei Patienten mit MPN zu erforschen und suchen mit genetischen Methoden nach bisher nicht bekannten Mutationen, die bei vererbten Formen von MPN eine ursächliche Rolle spielen.

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 entwickelnden Therapieansätzen, die gezielter die malignen Stammzellen angreifen.

 


Direct link to Lay Summary Last update: 15.08.2013

Responsible applicant and co-applicants

Publications

Publication
Homozygous calreticulin mutations in patients with myelofibrosis lead to acquired myeloperoxidase deficiency.
Theocharides Alexandre P A, Lundberg Pontus, Lakkaraju Asvin K K, Lysenko Veronika, Myburgh Renier, Aguzzi Adriano, Skoda Radek C, Manz Markus G (2016), Homozygous calreticulin mutations in patients with myelofibrosis lead to acquired myeloperoxidase deficiency., in Blood, 127(25), 3253-9.
Loss of Ezh2 synergizes with JAK2-V617F in initiating myeloproliferative neoplasms and promoting myelofibrosis.
Shimizu Takafumi, Kubovcakova Lucia, Nienhold Ronny, Zmajkovic Jakub, Meyer Sara C, Hao-Shen Hui, Geier Florian, Dirnhofer Stephan, Guglielmelli Paola, Vannucchi Alessandro M, Feenstra Jelena D Milosevic, Kralovics Robert, Orkin Stuart H, Skoda Radek C (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.
ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation.
Hammarén Henrik M, Ungureanu Daniela, Grisouard Jean, Skoda Radek C, Hubbard Stevan R, Silvennoinen Olli (2015), ATP binding to the pseudokinase domain of JAK2 is critical for pathogenic activation., in Proceedings of the National Academy of Sciences of the United States of America, 112(15), 4642-7.
Deletion of Stat3 in hematopoietic cells enhances thrombocytosis and shortens survival in a JAK2-V617F mouse model of MPN.
Grisouard Jean, Shimizu Takafumi, Duek Adrian, Kubovcakova Lucia, Hao-Shen Hui, Dirnhofer Stephan, Skoda Radek C (2015), Deletion of Stat3 in hematopoietic cells enhances thrombocytosis and shortens survival in a JAK2-V617F mouse model of MPN., in Blood, 125(13), 2131-40.
Mutational profile of childhood myeloproliferative neoplasms.
Karow A, Nienhold R, Lundberg P, Peroni E, Putti M C, Randi M L, Skoda R C (2015), Mutational profile of childhood myeloproliferative neoplasms., in Leukemia, 29(12), 2407-9.
Pathogenesis of myeloproliferative neoplasms.
Skoda Radek C, Duek Adrian, Grisouard Jean (2015), Pathogenesis of myeloproliferative neoplasms., in Experimental hematology, 43(8), 599-608.
Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms.
Lundberg Pontus, Karow Axel, Nienhold Ronny, Looser Renate, Hao-Shen Hui, Nissen Ina, Girsberger Sabine, Lehmann Thomas, Passweg Jakob, Stern Martin, Beisel Christian, Kralovics Robert, Skoda Radek C (2014), Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms., in Blood, 123(14), 2220-8.
Estrogen signaling selectively induces apoptosis of hematopoietic progenitors and myeloid neoplasms without harming steady-state hematopoiesis.
Sánchez-Aguilera Abel, Arranz Lorena, Martín-Pérez Daniel, García-García Andrés, Stavropoulou Vaia, Kubovcakova Lucia, Isern Joan, Martín-Salamanca Sandra, Langa Xavier, Skoda Radek C, Schwaller Jürg, Méndez-Ferrer Simón (2014), Estrogen signaling selectively induces apoptosis of hematopoietic progenitors and myeloid neoplasms without harming steady-state hematopoiesis., in Cell stem cell, 15(6), 791-804.
Loss of Stat1 decreases megakaryopoiesis and favors erythropoiesis in a JAK2-V617F-driven mouse model of MPNs.
Duek Adrian, Lundberg Pontus, Shimizu Takafumi, Grisouard Jean, Karow Axel, Kubovcakova Lucia, Hao-Shen Hui, Dirnhofer Stephan, Skoda Radek C (2014), Loss of Stat1 decreases megakaryopoiesis and favors erythropoiesis in a JAK2-V617F-driven mouse model of MPNs., in Blood, 123(25), 3943-50.
Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F.
Lundberg Pontus, Takizawa Hitoshi, Kubovcakova Lucia, Guo Guoji, Hao-Shen Hui, Dirnhofer Stephan, Orkin Stuart H, Manz Markus G, Skoda Radek C (2014), Myeloproliferative neoplasms can be initiated from a single hematopoietic stem cell expressing JAK2-V617F., in The Journal of experimental medicine, 211(11), 2213-30.
Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms.
Arranz Lorena, Sánchez-Aguilera Abel, Martín-Pérez Daniel, Isern Joan, Langa Xavier, Tzankov Alexandar, Lundberg Pontus, Muntión Sandra, Tzeng Yi-Shiuan, Lai Dar-Ming, Schwaller Jürg, Skoda Radek C, Méndez-Ferrer Simón (2014), Neuropathy of haematopoietic stem cell niche is essential for myeloproliferative neoplasms., in Nature, 512(7512), 78-81.
Selective deletion of Jak2 in adult mouse hematopoietic cells leads to lethal anemia and thrombocytopenia.
Grisouard Jean, Hao-Shen Hui, Dirnhofer Stephan, Wagner Kay-Uwe, Skoda Radek C (2014), Selective deletion of Jak2 in adult mouse hematopoietic cells leads to lethal anemia and thrombocytopenia., in Haematologica, 99(4), 52-4.
Somatic mutations in calreticulin can be found in pedigrees with familial predisposition to myeloproliferative neoplasms.
Lundberg Pontus, Nienhold Ronny, Ambrosetti Achille, Cervantes Francisco, Pérez-Encinas Manuel M, Skoda Radek C (2014), Somatic mutations in calreticulin can be found in pedigrees with familial predisposition to myeloproliferative neoplasms., in Blood, 123(17), 2744-5.
Complex subclone structure that responds differentially to therapy in a patient with essential thrombocythemia and chronic myeloid leukemia.
Grisouard Jean, Ojeda-Uribe Mario, Looser Renate, Hao-Shen Hui, Lundberg Pontus, Duek Adrian, Jeandidier Eric, Karow Axel, Skoda Radek C (2013), Complex subclone structure that responds differentially to therapy in a patient with essential thrombocythemia and chronic myeloid leukemia., in Blood, 122(22), 3694-6.
Differential effects of hydroxyurea and INC424 on mutant allele burden and myeloproliferative phenotype in a JAK2-V617F polycythemia vera mouse model.
Kubovcakova Lucia, Lundberg Pontus, Grisouard Jean, Hao-Shen Hui, Romanet Vincent, Andraos Rita, Murakami Masato, Dirnhofer Stephan, Wagner Kay-Uwe, Radimerski Thomas, Skoda Radek C (2013), Differential effects of hydroxyurea and INC424 on mutant allele burden and myeloproliferative phenotype in a JAK2-V617F polycythemia vera mouse model., in Blood, 121(7), 1188-99.

Collaboration

Group / person Country
Types of collaboration
Prof. Vladan Cokic, University of Belgrade, Serbia Serbien (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
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. Anders Waage, University of Trondheim, Norway Norway (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Magnus Björkholm, Karolinska Institute, Sweden Sweden (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
Dr. Francesco Passamonti, University of Varese, Italy Italy (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. Christian Beisel, D-BSSE, ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Dr. M. Perez-Encinas, Santiago de Compostela, Spain Spain (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. A. Tichelli, Diagnostic Hematology, University Hospital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Jakob Passweg, Division of Hematology, University Hospital Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results

Associated projects

Number Title Start Funding scheme
135712 Genetic analysis of myeloproliferative disorders 01.06.2011 Project funding (Div. I-III)
166613 Genetic analysis of myeloproliferative neoplasms 01.06.2016 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

Abstract

Myeloproliferative neoplasms (MPN) are a group of diseases characterized by aberrant proliferation of the erythroid, megakaryocytic and myeloid lineages. They represent clonal stem cell disorders with an inherent tendency towards leukemic transformation. MPN are subdivided into three disease entities: polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The report on the frequent occurrence of a somatic mutation in the Janus kinase 2 gene (JAK2-V617F) in patients with MPN has increased our understanding of the pathogenesis, improved the diagnostic workup and allowed developing JAK2 inhibitors for the treatment of late stages of MPN. There is now convincing evidence for the existence of additional mutations that precede the acquisition of JAK2-V617F and that are likely to be involved in initiating the disease in a proportion of MPN patients. These mutations can be either somatic, e.g. in genes that are involved in epigenetic regulation (e.g. EZH2), or germline in families with a predisposition to acquire MPN. In familial MPN, somatic mutations (most frequently JAK2-V617F) are required for initiating MPN. It is not clear yet, whether in sporadic MPN a single somatic event such as JAK2-V617F may be sufficient or if several mutations must collaborate to initiate MPN. We have developed several mouse models that will allow us to address these questions and should clarify the requirements for disease initiation. In addition, we will study the question how different JAK2 mutations that signal through the same kinase domain generate different phenotypes (ET versus PV). We have adapted the new sequencing technologies to define the mutational status of the MPN cells in large cohorts of MPN patients and familial cases. We now have a collection of extensively characterized primary cells to test some of the hypotheses derived from our mouse models and familial MPN studies. The proposed experiments will address the following specific aims:1. To examine correlations between somatic mutations and disease complication and progression in a cohort of MPN patients extensively characterized by next generation sequencing2. To examine the role of critical downstream signaling mediators such as the STAT proteins in ET versus PV phenotype decisions 3. To test the potential synergism between JAK2-V617F and loss of function mutations in EZH2 in disease initiation and progression4. To search for novel disease causing mutations in familial MPNSignificance: The new sequencing technologies allow to characterize large cohorts of patients for mutations in disease related genes. This opens the possibility to stratify patients in risk groups based on their mutational status and improve individualized predictions and therapeutic decisions. The signaling studies can potentially contribute to better understanding why mutations in JAK2 proteins can result in different phenotypes and may also identify interactions that are specific for the mutated JAK2. These could represent targets for specific intervention. The factors and mechanisms influencing disease initiation of MPN are poorly understood. Knowing the initiating events and elucidating the function of collaborating mutations will be important to devise new approached to improve prognosis and ultimately treatment of patients with MPN. These additional mutated genes may constitute new drug targets in MPN.
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