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Determination of the mutational landscape and clonal architecture and its application in angiogenesis and thrombosis of MPN patients

English title Determination of the mutational landscape and clonal architecture and its application in angiogenesis and thrombosis of MPN patients
Applicant Skoda Radek
Number 152420
Funding scheme SCOPES
Research institution Departement Biomedizin Universität Basel
Institution of higher education University of Basel - BS
Main discipline Pathophysiology
Start/End 01.04.2014 - 30.06.2017
Approved amount 105'000.00
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Keywords (4)

myeloproliferative neoplasms; thrombosis; mutational profile; acute leukemia

Lay Summary (German)

Lead
Myeloproliferative Erkrankungen (MPD) sind Blutkrankheiten die mit einer Vermehrung von weissen und roten Blutzellen sowie von Blutplättchen einhergehen und in Leukämie übergehen können. Dazu gehören die sogenannte Polyzythämie, die Thrombozythämie und die idiopathische Myelofibrose. Es gibt bisher keine Therapie, die diese Krankheiten heilen kann. Das Ziel unserer Forschung ist es die krankheitsverursachenden Veränderungen auf molekularer Ebene zu verstehen, damit nach neuen Therapieformen gesucht werden kann.
Lay summary

Bei rund drei Viertel der Patienten mit MPN Erkrankungen haben wir in den blutbildenden Stammzellen eine erworbene Mutation im signalübermittelnden Enzym Janus-Kinase 2 (JAK2) entdeckt. Auch Mutationen im Calreticulin (CALR) Gen und im Gen für den Thromopoetinrezeptor MPL sind bei einem Viertel der Patienten/innen kausal mit der Krankheitsentstehung verknüpft. Inzwischen sind mehr als 20 zusätzliche Genmutationen bekannt, die bei einem Teil der MPN Patienten/innen gelegentlich zusammen der JAK2, CALR oder MPL Mutation auftreten können. Um die Bedeutung dieser zusätzlichen Mutationen für den Krankheitsverlauf zu studieren, haben wir Methoden entwickelt, um simultan nach Mutationen in einer grösseren Zahl von Genen in Gruppen von Patienten/innen zu suchen. Das vorliegende Projekt soll die Frage untersuchen, welche der erworbenen Mutationen Voraussagen betreffend Krankheitsverlauf und Prognose der MPN Erkrankung erlauben. Diese Studie wir in Zusammenarbeit mit dem Universitätsspital in Belgrad, Serbien durchgeführt. Insbesondere sollen Patienten/innen gleich bei Diagnosestellung eingeschlossen werden und dann prospektiv bezüglich Krankheitsverlauf nachverfolgt werden. Dadurch hoffen wir Kriterien zu etablieren, die für die Prognosestellung und Auswahl der besten Therapie herangezogen werden können.

Direct link to Lay Summary Last update: 04.04.2014

Responsible applicant and co-applicants

Publications

Publication
Bone marrow microvessel density and plasma angiogenic factors in myeloproliferative neoplasms: clinicopathological and molecular correlations.
Leković D, Gotić M, Skoda R, Beleslin-Čokić B, Milic N, Mitrović-Ajtic O, Nienhold R, Sefer D, Subotički T, Buac M, Marković D, Diklić M, Čokić VP (2017), Bone marrow microvessel density and plasma angiogenic factors in myeloproliferative neoplasms: clinicopathological and molecular correlations., in Ann. Hematol., 96, 393-404.
Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms.
Subotički Tijana, Ajtić Olivera Mitrović, Beleslin-Čokić Bojana B, Nienhold Ronny, Diklić Miloš, Đikić Dragoslava, Leković Danijela, Bulat Tanja, Marković Dragana, Gotić Mirjana, Noguchi Constance T, Schechter Alan N, Skoda Radek C, Čokić Vladan P, Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms., in Molecular carcinogenesis, 56, 567-579.

Collaboration

Group / person Country
Types of collaboration
Institute for Medical Research Serbien (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
Dr. Christian Beisel, D-BSSE, ETH Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
22nd Annual Congress of EHA Individual talk What's new in MPN? 22.06.2017 Madrid, Spain Cokic Vladan P.; Skoda Radek;
MPN&MPNr-EuroNet Twelfth Meeting Individual talk Genomic and epigenomic analyses of triple negative MPNs 10.05.2017 Göteborg, Sweden Cokic Vladan P.;


Associated projects

Number Title Start Funding scheme
166613 Genetic analysis of myeloproliferative neoplasms 01.06.2016 Project funding (Div. I-III)
147016 Genetic analysis of myeloproliferative neoplasms 01.06.2013 Project funding (Div. I-III)

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. The frequent occurrence of a somatic mutation in the Janus kinase 2 gene (JAK2-V617F) in patients with MPN has a major impact on diagnosis and therapy of patients with MPN. During the last years several mutations in genes other than JAK2 have been described. Mainly, mutations in genes involved in regulation of the epigenetic machinery, such as TET2, EZH2 and DNTM3A have been reported. These gene mutations are not restricted to MPN, but are also found in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Improvement of sequencing technology, namely the introduction of Next Generation Sequencing (NGS) has massively increased the sequencing power. This has enabled large genome wide studies as well as targeted sequencing studies in large cohorts of patients that are not feasible with classical capillary DNA sequencing. Thus, a more complete picture of the genetic alterations that are present in the malignant cells can be obtained and the synergy between several mutations in the same patient can be studied. We have established a method to efficiently sequence large number of patients for a specific set up genes using and enrichment based NGS strategy. Using this method to screen for somatic mutations, we will reveal whether patients can be risk stratified based on their mutational status and what mutations might predispose to deregulated angiogenesis and thrombosis. We will provide insight into the role of aberrantly expressed angiogenic factors as well as prothrombogenic genetic and molecular markers and their correlation with the mutational profile of patients with MPN. The project results will contribute to a better understanding of the pathogenesis of MPN and will increasingly become the basis for individual therapeutic decisions in the near future. Besides a great benefit for the general efforts in fighting cancer, networking between Switzerland and Serbian research centers will allow transfer of knowledge and technology between participants, mobility of human resources, education and promotion of young researchers.
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