myeloproliferative disorders; hematopoiesis; chromosomal aberrations; transgenic mice; Janus kinase
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.
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.
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.
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.
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.
Skoda Radek C, Duek Adrian, Grisouard Jean (2015), Pathogenesis of myeloproliferative neoplasms., in Experimental hematology
, 43(8), 599-608.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.