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Genetic analysis of myeloproliferative disorders

English title Genetic analysis of myeloproliferative disorders
Applicant Skoda Radek
Number 135712
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 01.06.2011 - 31.05.2013
Approved amount 380'000.00
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All Disciplines (2)

Discipline
Experimental Cancer Research
Genetics

Keywords (4)

hematopoiesis; myeloproliferative disorders; Janus kinase 2; transgenic mice

Lay Summary (English)

Lead
Lay summary

Genetic Analysis ofMyeloproliferative Disorders 

Prof. Dr. Radek Skoda, Department of Biomedicine,Experimental Hematology, University Hospital Basel

Myeloproliferative neoplasms (MPN) is a group of blooddiseases characterized by overproduction of white blood cells, red blood cellsand platelets. At present there is no cure for this group of disorders and aftera variable latency, MPN can transform into acute leukemia. We found that inabout 70-80% of MPN patients the blood stem cells carry a mutation in the gene “Janus kinase 2 (JAK2)”. JAK2 is anenzyme that transmits signals coming from the outside into the cell. Themutation in JAK2 (JAK2-V617) amplifies the growthpromoting effect of these signals so that more blood cells are formed. Theenzymatic activity JAK2 can beinhibited by drugs and such JAK2 inhibitors are now being tested in clinicaltrials. MPN consists of 3 entities called polycythemia vera (PV), essentialthrombocythemia (ET) and primary myelofibrosis (PMF). It remains unknown whythe JAK2-V617 mutation can cause suchdifferent manifestations of MPN and we are currently investigating thisquestion. Furthermore, we gained evidence that JAK2-V617 may be acting together with other as yet unknownmutations and we are attempting to identify such mutations through moleculargenetic analysis. Furthermore, we are studying rare familial cases of MPN inwhich an increased likelihood for acquiring such a JAK2 mutation is inherited. Knowledge of these mechanisms will beimportant in assessing the risk of complications for patients with MPN andmaking therapeutic decisions. Furthermore, additional genes mutated in MPN mayconstitute targets for developing new drugs.

KEYWORDS

Hematopoiesis, Januskinase 2, myeloproliferative neoplasms (MPN) 

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Differential effects of hydroxyurea and INC424 on mutant allele burden and myeloproliferative phenotype in a JAK2-V617F polycythemia vera mouse model
Kubovcakova Lucia (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), 1188-1199.
The DEAH-box helicase RHAU is an essential gene and critical for mouse hematopoiesis.
Lai Janice Ching, Ponti Svetlana, Pan Dejing, Kohler Hubertus, Skoda Radek C, Matthias Patrick, Nagamine Yoshikuni (2012), The DEAH-box helicase RHAU is an essential gene and critical for mouse hematopoiesis., in Blood, 119(18), 4291-4300.
The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling.
Ungureanu Daniela, Wu Jinhua, Pekkala Tuija, Niranjan Yashavanthi, Young Clifford, Jensen Ole N, Xu Chong-Feng, Neubert Thomas A, Skoda Radek C, Hubbard Stevan R, Silvennoinen Olli (2011), The pseudokinase domain of JAK2 is a dual-specificity protein kinase that negatively regulates cytokine signaling., in Nature structural & molecular biology, 18(9), 971-976.
Biphasic roles for soluble guanylyl cyclase (sGC) in platelet activation.
Zhang Guoying, Xiang Binggang, Dong Anping, Skoda Radek C, Daugherty Alan, Smyth Susan S, Du Xiaoping, Li Zhenyu (2011), Biphasic roles for soluble guanylyl cyclase (sGC) in platelet activation., in Blood, 118(13), 3670-3679.
SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis.
Chagraoui Hedia, Kassouf Mira, Banerjee Sreemoti, Goardon Nicolas, Clark Kevin, Atzberger Ann, Pearce Andrew C, Skoda Radek C, Ferguson David J P, Watson Steve P, Vyas Paresh, Porcher Catherine (2011), SCL-mediated regulation of the cell-cycle regulator p21 is critical for murine megakaryopoiesis., in Blood, 118(3), 723-735.

Associated projects

Number Title Start Funding scheme
147016 Genetic analysis of myeloproliferative neoplasms 01.06.2013 Project funding (Div. I-III)
120724 Genetic analysis of myeloproliferative disorders 01.06.2008 Project funding (Div. I-III)

Abstract

Myeloproliferative disorders (MPD) is a group of blood diseases characterized by overproduction of white blood cells, red blood cells and platelets. Our research project aims at understanding the disease causing alteration at the molecular level in order to search for new ways of treating the disease.MPD consists of 3 entities called polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). At present there is no cure for this group of disorders. We found that in about 70-80% of MPD patients the blood stem cells carry a mutation in the gene “Janus kinase 2 (JAK2)”. JAK2 is an enzyme that transmits signals coming from the outside into the cell and the mutation in JAK2 (JAK2-V617) amplifies the growth promoting effect of these signals so that more blood cells are formed. Therefore, the mutated JAK2 represents a potential target for small molecules that could bind and inhibit the activated JAK2. Currently it is unknown why the JAK2-V617 mutation can cause 3 different manifestations of MPD, namely PV, ET or PMF. Furthermore, we gained evidence that JAK2-V617 may be acting together with other as yet unknown mutations. Although the JAK2 mutation is not inherited to the next generation and is only acquired in the blood cells, there are families in which an increased likelihood for acquiring such a JAK2 mutation.The proposed project aims at defining why the JAK2 mutation can cause 3 different forms of the disease. We hypothesize that additional factors modify the effects of the JAK2 mutation and we will try to identify those factors. In addition, we are searching for the genetic alterations that precede the acquisition of JAK2 mutations by genetic analysis in families with MPD. Knowledge of these mechanisms will be important in assessing the risk of complications for patients with MPD and making therapeutic decisions. If mutations in as yet unknown gene(s) precede the acquisition of JAK2-V617F, we may expect that Jak2 inhibitors will not cure the disease, but rather reset MPD to a pre-clinical stage. Furthermore, additional genes mutated in MPD may constitute new drug targets.
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