Search

Your search keyword '"Kubovcakova, Lucia"' showing total 44 results
Start Over Author "Kubovcakova, Lucia"
44 results on '"Kubovcakova, Lucia"'

2. Iron is a modifier of the phenotypes of JAK2-mutant myeloproliferative neoplasms

Author

Stetka, Jan, Usart, Marc, Kubovcakova, Lucia, Rai, Shivam, Rao, Tata Nageswara, Sutter, Joshua, Hao-Shen, Hui, Dirnhofer, Stefan, Geier, Florian, Bader, Michael S., Passweg, Jakob R., Manolova, Vania, Dürrenberger, Franz, Ahmed, Nouraiz, Schroeder, Timm, Ganz, Tomas, Nemeth, Elizabeta, Silvestri, Laura, Nai, Antonella, Camaschella, Clara, and Skoda, Radek C.

Published
2023
Full Text
View/download PDF

3. JAK2-V617F and interferon-α induce megakaryocyte-biased stem cells characterized by decreased long-term functionality

Author

Rao, Tata Nageswara, Hansen, Nils, Stetka, Jan, Luque Paz, Damien, Kalmer, Milena, Hilfiker, Julian, Endele, Max, Ahmed, Nouraiz, Kubovcakova, Lucia, Rybarikova, Margareta, Hao-Shen, Hui, Geier, Florian, Beisel, Christian, Dirnhofer, Stefan, Schroeder, Timm, Brümmendorf, Tim H., Wolf, Dominik, Koschmieder, Steffen, and Skoda, Radek C.

Published
2021
Full Text
View/download PDF

4. Loss of Dnmt3a increased self-renewal and resistance to pegIFNα in JAK2-V617F-positive myeloproliferative neoplasms

Author

Usart, Marc, primary, Stetka, Jan, additional, Luque Paz, Damien, additional, Hansen, Nils, additional, Kimmerlin, Quentin, additional, Almeida Fonseca, Tiago, additional, Lock, Melissa, additional, Kubovcakova, Lucia, additional, Karjalainen, Riikka, additional, Hao-Shen, Hui, additional, Börsch, Anastasiya, additional, El Taher, Athimed, additional, Schulz, Jessica, additional, Leroux, Jean-Christophe, additional, Dirnhofer, Stefan, additional, and Skoda, Radek C., additional

Published
2024
Full Text
View/download PDF

5. Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms

Author

Nieborowska-Skorska, Margaret, Maifrede, Silvia, Dasgupta, Yashodhara, Sullivan, Katherine, Flis, Sylwia, Le, Bac Viet, Solecka, Martyna, Belyaeva, Elizaveta A., Kubovcakova, Lucia, Nawrocki, Morgan, Kirschner, Martin, Zhao, Huaqing, Prchal, Josef T., Piwocka, Katarzyna, Moliterno, Alison R., Wasik, Mariusz, Koschmieder, Steffen, Green, Tony R., Skoda, Radek C., and Skorski, Tomasz

Published
2017
Full Text
View/download PDF

12. JAK2-V617F and interferon-�� induce megakaryocyte-biased stem cells characterized by decreased long-term functionality

Author

Tata, Nageswara Rao, Hansen, Nils, Stetka, Jan, Luque Paz, Damien, Kalmer, Milena, Hilfiker, Julian, Endele, Max, Ahmed, Nouraiz, Kubovcakova, Lucia, Rybarikova, Margareta, Hao-Shen, Hui, Geier, Florian, Beisel, Christian, Dirnhofer, Stefan, Schroeder, Timm, Br��mmendorf, Tim H, Wolf, Dominik, Koschmieder, Steffen, and Skoda, Radek C

Subjects
hemic and immune systems, 610 Medicine & health
Abstract

We studied a subset of hematopoietic stem cells (HSCs) that are defined by elevated expression of CD41 (CD41hi) and showed bias for differentiation toward megakaryocytes (Mks). Mouse models of myeloproliferative neoplasms (MPNs) expressing JAK2-V617F (VF) displayed increased frequencies and percentages of the CD41hi vs CD41lo HSCs compared with wild-type controls. An increase in CD41hi HSCs that correlated with JAK2-V617F mutant allele burden was also found in bone marrow from patients with MPN. CD41hi HSCs produced a higher number of Mk-colonies of HSCs in single-cell cultures in vitro, but showed reduced long-term reconstitution potential compared with CD41lo HSCs in competitive transplantations in vivo. RNA expression profiling showed an upregulated cell cycle, Myc, and oxidative phosphorylation gene signatures in CD41hi HSCs, whereas CD41lo HSCs showed higher gene expression of interferon and the JAK/STAT and TNF��/NF��B signaling pathways. Higher cell cycle activity and elevated levels of reactive oxygen species were confirmed in CD41hi HSCs by flow cytometry. Expression of Epcr, a marker for quiescent HSCs inversely correlated with expression of CD41 in mice, but did not show such reciprocal expression pattern in patients with MPN. Treatment with interferon-�� further increased the frequency and percentage of CD41hi HSCs and reduced the number of JAK2-V617F+ HSCs in mice and patients with MPN. The shift toward the CD41hi subset of HSCs by interferon-�� provides a possible mechanism of how interferon-�� preferentially targets the JAK2 mutant clone.

Published
2021
Full Text
View/download PDF

23. Aging of Bone Marrow Microenvironment Promotes Myeloid Bias of Hematopoietic Progenitors and Is a Target in Age-Related Myeloproliferative Neoplasms

Author

Ho, Ya-Hsuan, primary, del Toro, Raquel, additional, Rivera-Torres, José, additional, Rak, Justyna, additional, Korn, Claudia, additional, García-García, Andrés, additional, Kubovcakova, Lucia, additional, Macías, David, additional, Arranz, Lorena, additional, González-Gómez, Cristina, additional, Wittner, Monika, additional, Nienhold, Ronny, additional, Waller, Amie K, additional, Foster, Holly R, additional, Lopez-Otin, Carlos, additional, Johnson, Randall S, additional, Nerlov, Claus, additional, Vainchenker, William, additional, Ghevaert, Cedric, additional, Louache, Fawzia, additional, Skoda, Radek C., additional, Andrés, Vicente, additional, and Mendez-Ferrer, Simon, additional

Published
2018
Full Text
View/download PDF

24. HSP27 is a partner of JAK2-STAT5 and a potential therapeutic target in myelofibrosis

Author

Sevin, Margaux, primary, Kubovcakova, Lucia, additional, Pernet, Nicolas, additional, Causse, Sébastien, additional, Vitte, Franck, additional, Villeval, Jean Luc, additional, Lacout, Catherine, additional, Cordonnier, Marine, additional, Rodrigues-Lima, Fernando, additional, Chanteloup, Gaétan, additional, Mosca, Matthieu, additional, Chrétien, Marie-Lorraine, additional, Bastie, Jean Noël, additional, Audia, Sylvain, additional, Sagot, Paul, additional, Ramla, Selim, additional, Martin, Laurent, additional, Gleave, Martin, additional, Mezger, Valérie, additional, Skoda, Radek, additional, Plo, Isabelle, additional, Garrido, Carmen, additional, Girodon, François, additional, and de Thonel, Aurélie, additional

Published
2018
Full Text
View/download PDF

25. Loss of Ezh2 synergizes with JAK2-V617F in initiating myeloproliferative neoplasms and promoting myelofibrosis

Author

Shimizu, Takafumi, primary, Kubovcakova, Lucia, additional, Nienhold, Ronny, additional, Zmajkovic, Jakub, additional, Meyer, Sara C., additional, Hao-Shen, Hui, additional, Geier, Florian, additional, Dirnhofer, Stephan, additional, Guglielmelli, Paola, additional, Vannucchi, Alessandro M., additional, Feenstra, Jelena D. Milosevic, additional, Kralovics, Robert, additional, Orkin, Stuart H., additional, and Skoda, Radek C., additional

Published
2016
Full Text
View/download PDF

26. Loss of Dnmt3aincreases self-renewal and resistance to pegIFN-α in JAK2-V617F–positive myeloproliferative neoplasms

Author

Usart, Marc, Stetka, Jan, Paz, Damien Luque, Hansen, Nils, Kimmerlin, Quentin, Fonseca, Tiago Almeida, Lock, Melissa, Kubovcakova, Lucia, Karjalainen, Riikka, Hao-Shen, Hui, Börsch, Anastasiya, El Taher, Athimed, Schulz, Jessica, Leroux, Jean-Christophe, Dirnhofer, Stefan, and Skoda, Radek C.

Abstract

•Loss of Dnmt3aincreases self-renewal of JAK2-V617F HSCs and mitigates their attrition upon chronic pegIFN-α treatment.•A combination of pegIFN-α and 5-azacytidine can strongly decrease the JAK2-mutant allele burden in MPN driven by JAK2-V617F alone.

Published
2024
Full Text
View/download PDF

28. JAK2V617F and Loss of Ezh2 in Hematopoietic Cells Contribute Synergistically to Myeloproliferative Neoplasm Initiation Potential, and Accelerate Progression of Disease

Author

Shimizu, Takafumi, primary, Hao-Shen, Hui, additional, Kubovcakova, Lucia, additional, Lundberg, Pontus, additional, Dirnhofer, Stephan, additional, Orkin, Stuart H., additional, Grisouard, Jean, additional, Shimizu, Yukiko, additional, Pianta, Annalisa, additional, Szczerba, Barbara, additional, Nienhold, Ronny, additional, and Skoda, Radek C., additional

Published
2014
Full Text
View/download PDF

36. JAK2 exon 12mutant mice display isolated erythrocytosis and changes in iron metabolism favoring increased erythropoiesis

Author

Grisouard, Jean, Li, Sai, Kubovcakova, Lucia, Rao, Tata Nageswara, Meyer, Sara C., Lundberg, Pontus, Hao-Shen, Hui, Romanet, Vincent, Murakami, Masato, Radimerski, Thomas, Dirnhofer, Stephan, and Skoda, Radek C.

Abstract

Mutations in JAK2 exon 12are frequently found in patients with polycythemia vera (PV) that do not carry a JAK2-V617Fmutation. The majority of these patients display isolated erythrocytosis. We generated a mouse model that expresses JAK2-N542-E543del,the most frequent JAK2 exon 12mutation found in PV patients. Mice expressing the human JAK2-N542-E543del (Ex12)showed a strong increase in red blood cell parameters but normal neutrophil and platelet counts, and reduced overall survival. Erythropoiesis was increased in the bone marrow and spleen, with normal megakaryopoiesis and absence of myelofibrosis in histopathology. Erythroid progenitors and precursors were increased in hematopoietic tissues, but the numbers of megakaryocytic precursors were unchanged. Phosphorylation Stat3 and Erk1/2 proteins were increased, and a trend toward increased phospho-Stat5 and phospho-Stat1 was noted. However, Stat1 knock out in Ex12mice induced no changes in platelet or red cell parameters, indicating that Stat1 does not play a central role in mediating the effects of Ex12 signaling on megakaryopoiesis or erythropoiesis. Ex12mice showed decreased expression of hepcidinand increased expression of transferrin receptor-1and erythroferrone,suggesting that the strong erythroid phenotype in Ex12mutant mice is favored by changes in iron metabolism that optimize iron availability to allow maximal production of red cells.

Published
2016
Full Text
View/download PDF

37. Deletion of Stat3in hematopoietic cells enhances thrombocytosis and shortens survival in a JAK2-V617F mouse model of MPN

Author

Grisouard, Jean, Shimizu, Takafumi, Duek, Adrian, Kubovcakova, Lucia, Hao-Shen, Hui, Dirnhofer, Stephan, and Skoda, Radek C.

Abstract

The acquired somatic JAK2-V617F mutation is present in >80% of patients with myeloproliferative neoplasms (MPNs). Stat3plays a role in hematopoietic homeostasis and might influence the JAK2-V617F–driven MPN phenotype. We crossed our transgenic SclCre;V617Fmice with a conditional Stat3knockout strain and performed bone marrow transplantations into lethally irradiated recipient mice. The deletion of Stat3increased the platelet numbers in SclCre;V617F;Stat3fl/flmice compared with SclCre;V617F;Stat3fl/+or SclCre;V617F;Stat3+/+mice. Stat3deletion also normalized JAK2-V617F–induced neutrophilia. Megakaryocyte progenitors were elevated, especially in the spleen, and a slight increase in myelofibrosis was noted. We observed increased mRNA expression levels of Stat1and Stat1target genes and augmented phosphorylation of Stat1protein in bone marrow and spleen of JAK2-V617F mice after Stat3deletion. The survival of Stat3-deficient mice expressing JAK2-V617F was reduced. Inflammatory bowel disease, previously associated with shortened survival of Stat3-deficient mice, was less prominent in the bone marrow transplantation setting, possibly by limiting deletion of Stat3to hematopoietic tissues only. In conclusion, deletion of Stat3in hematopoietic cells from JAK2-V617F mice did not ameliorate the course of MPN, but rather enhanced thrombocytosis and shortened the overall survival.

Published
2015
Full Text
View/download PDF

38. Adrenergic modulation of the type 1 IP3 receptors in the rat heart

Author

Jurkovicova, Dana, Kubovcakova, Lucia, Hudecova, Sona, Kvetnansky, Richard, and Krizanova, Olga

Subjects
*INOSITOL phosphates, *CALCIUM, *INOSITOL, *CYTOKINES
Abstract

Abstract: Inositol 1,4,5-trisphosphate (IP3) receptors are calcium-releasing channels localized on the sarcoplasmic reticulum. IP3 receptors mediate the calcium mobilizing effect of a wide range of hormones, cytokines, and neurotransmitters and play an important role in variety of cell functions. The aim of this work was to study, how partial depletion of catecholamines affects the gene expression and protein levels of the type 1 IP3 receptors in rat heart. The type 1 IP3 receptor mRNA levels were studied in the left cardiac atrium and ventricle of rats treated with 6-hydroxydopamine (6-OHDA) in control and stressed conditions. The 6-OHDA produces anatomical and functional denervation resulting in decreased levels of noradrenaline and adrenaline. We also used corticoliberin (CRH) knockout mice, where secretion of adrenaline is significantly suppressed. Administration of 6-OHDA significantly decreases mRNA levels of the type 1 IP3 receptor in both, the left atrium and the left ventricle, while the gene expression of the sarcoplasmic reticular Ca2+-ATPase (SERCA 2) was unaffected. CRH knockout mice possess markedly lower levels of the type 1 IP3 receptor mRNA compared to wild-type mice in both, control and stressed conditions. These data point to the adrenergic modulation of the type 1 IP3 receptors in the rat hearts. [Copyright &y& Elsevier]

Published
2006
Full Text
View/download PDF

39. Repeated Immobilization Stress Decreases mRNA and Protein Levels of the Type 1 IP3 Receptor in Rat Heart.

Author

KREPSOVA, KATARINA, MICUTKOVA, LUCIA, NOVOTOVA, MARTA, KUBOVCAKOVA, LUCIA, KVETNANSKY, RICHARD, and KRIZANOVA, OLGA

Subjects
LABORATORY rats, GENE expression, MESSENGER RNA, PHOSPHOINOSITIDES, HEART atrium
Abstract

Stress is one of the major contributors to the development of cardiovascular disorders and psychiatric illnesses. Immobilization stress belongs to severe stressors and is known to activate several calcium transport systems. The aim of this work was to determine whether repeated immobilization stress changes mRNA and protein levels of the type 1 and 2 inositol-1,4,5-trisphosphate (IP3 ) receptors in cardiac tissue. Rats were immobilized for 7 days, 2 h daily. After repeated immobilization, increased numbers of collagen fibers were accumulated in the heart atria compared to hearts of the control group of rats. Gene expression was determined after reverse transcription and subsequent real-time polymerase chain reaction, using SYBR Green fluorescent dye. Protein levels were determined by Western blot and hybridization with the primary antibody against IP3 receptors. Contrary to single immobilization, repeated immobilization decreased a gene expression of the type 1 and 2 IP3 receptors, and also protein levels of the IP3 receptors. Although the physiologic relevance of our observations remains to be elucidated, we propose that the decrease in IP3 receptors may have an impact on the development of the pathophysiologic changes in the heart. [ABSTRACT FROM AUTHOR]

Published
2004
Full Text
View/download PDF

40. Loss of Stat1decreases megakaryopoiesis and favors erythropoiesis in a JAK2-V617F–driven mouse model of MPNs

Author

Duek, Adrian, Lundberg, Pontus, Shimizu, Takafumi, Grisouard, Jean, Karow, Axel, Kubovcakova, Lucia, Hao-Shen, Hui, Dirnhofer, Stephan, and Skoda, Radek C.

Abstract

The interferon-γ (IFNγ)/signal transducer and activator of transcription 1 (Stat1) pathway shows higher activity in patients with essential thrombocythemia (ET) than in polycythemia vera (PV) and was proposed to be promoting the ET phenotype. We explored the phenotypic consequences of Stat1deficiency on the effects of Janus kinase 2 (JAK2)–V617F in vivo by crossing mice expressing JAK2-V617F with Stat1knockout mice. JAK2-V617F;Stat1−/−double transgenic mice showed higher red cell parameters and lower platelet counts compared with JAK2-V617F;Stat1+/+mice. Bone marrow transplantation reproduced these phenotypic changes in wild-type recipients, demonstrating that the effect of Stat1 is cell-intrinsic and does not require a Stat1-deficient microenvironment. Deletion of Stat1increased burst-forming unit–erythroid and reduced colony-forming unit–megakaryocyte colony formation driven by JAK2-V617F, but was not sufficient to completely normalize the platelet count. Gata1, a key regulator of megakaryopoiesis and erythropoiesis, was decreased in Stat1-deficient platelets. V617Ftransgenic mice with thrombocytosis had higher serum levels of IFNγ than normal controls and patients with ET showed higher IFNγ serum levels than patients with PV. Together, these results support the concept that activating Stat1 in the presence of JAK2-V617F, for example, through IFNγ, constrains erythroid differentiation and promotes megakaryocytic development, resulting in ET phenotype.

Published
2014
Full Text
View/download PDF

42. Loss of Dnmt3aConfers Resistance to Pegifnα in JAK2-V617F Mouse Model

Author

Stetka, Jan, Hansen, Nils, Kubovcakova, Lucia, Hao-Shen, Hui, Dirnhofer, Stefan, and Skoda, Radek C.

Abstract

Myeloproliferative neoplasms (MPNs) are clonal hematological malignancies, which are initiated and maintained by a pool of malignant long-term hematopoietic stem cells (LT-HSCs). A recurrent gain-of-function mutation in JAK2-V617F (VF) is present in a majority of patients with MPN. Treatment with pegylated interferon alpha (pegIFNα) is currently the only therapy known to reduce JAK2-V617F+LT-HSCs and to induce a complete molecular remission (CMR) in a subset of patients. Long-term follow-up studies suggested, that patients with additional mutations in epigenetic modifiers, such as DNMT3A, have poorer responses to pegIFNα and are less likely to achieve CMR. We therefore hypothesized that DNMT3Aloss leads to alterations in JAK2-V617F HSCs functions conferring resistance to pegIFNα treatment.

Published
2020
Full Text
View/download PDF

43. Ruxolitinib-induced defects in DNA repair cause sensitivity to PARP inhibitors in myeloproliferative neoplasms

Author

Nieborowska-Skorska, Margaret, Maifrede, Silvia, Dasgupta, Yashodhara, Sullivan, Katherine, Flis, Sylwia, Le, Bac Viet, Solecka, Martyna, Belyaeva, Elizaveta A, Kubovcakova, Lucia, Nawrocki, Morgan, Kirschner, Martin, Zhao, Huaqing, Prchal, Josef T, Piwocka, Katarzyna, Moliterno, Alison R, Wasik, Mariusz, Koschmieder, Steffen, Green, Tony R, Skoda, Radek C, and Skorski, Tomasz

Subjects
Myeloproliferative Disorders, DNA Repair, food and beverages, Drug Synergism, Janus Kinase 2, Poly(ADP-ribose) Polymerase Inhibitors, Piperazines, 3. Good health, Cell Line, Mice, Pyrimidines, hemic and lymphatic diseases, Neoplasms, Nitriles, Tumor Cells, Cultured, Animals, Heterografts, Humans, Phthalazines, Pyrazoles, Calreticulin, Receptors, Thrombopoietin
Abstract

Myeloproliferative neoplasms (MPNs) often carry JAK2(V617F), MPL(W515L), or CALR(del52) mutations. Current treatment options for MPNs include cytoreduction by hydroxyurea and JAK1/2 inhibition by ruxolitinib, both of which are not curative. We show here that cell lines expressing JAK2(V617F), MPL(W515L), or CALR(del52) accumulated reactive oxygen species-induced DNA double-strand breaks (DSBs) and were modestly sensitive to poly-ADP-ribose polymerase (PARP) inhibitors olaparib and BMN673. At the same time, primary MPN cell samples from individual patients displayed a high degree of variability in sensitivity to these drugs. Ruxolitinib inhibited 2 major DSB repair mechanisms, BRCA-mediated homologous recombination and DNA-dependent protein kinase-mediated nonhomologous end-joining, and, when combined with olaparib, caused abundant accumulation of toxic DSBs resulting in enhanced elimination of MPN primary cells, including the disease-initiating cells from the majority of patients. Moreover, the combination of BMN673, ruxolitinib, and hydroxyurea was highly effective in vivo against JAK2(V617F)+ murine MPN-like disease and also against JAK2(V617F)+, CALR(del52)+, and MPL(W515L)+ primary MPN xenografts. In conclusion, we postulate that ruxolitinib-induced deficiencies in DSB repair pathways sensitized MPN cells to synthetic lethality triggered by PARP inhibitors.

44. Regulation of gene expression of catecholamine biosynthetic enzymes in dopamine-beta-hydroxylase- and CRH-knockout mice exposed to stress.

Author

Kvetnanský R, Krizanova O, Tillinger A, Sabban EL, Thomas SA, and Kubovcakova L

Subjects
Adrenal Medulla physiology, Animals, Female, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Restraint, Physical, Signal Transduction physiology, Stellate Ganglion physiology, Catecholamines metabolism, Corticotropin-Releasing Hormone genetics, Corticotropin-Releasing Hormone metabolism, Dopamine beta-Hydroxylase genetics, Dopamine beta-Hydroxylase metabolism, Gene Expression Regulation, Enzymologic, Phenylethanolamine N-Methyltransferase genetics, Phenylethanolamine N-Methyltransferase metabolism, Stress, Psychological, Tyrosine 3-Monooxygenase genetics, Tyrosine 3-Monooxygenase metabolism
Abstract

Norepinephrine-deficient mice harbor a disruption of the gene for dopamine-beta-hydroxylase (DBH-KO). Corticotropin-releasing hormone knockout mice (CRH-KO) have markedly reduced HPA activity. The aim of the present work was to study how deficiency of DBH and CRH would affect tyrosine hydroxylase (TH), DBH, and phenylethanolamine N-methyltransferase (PNMT) gene expression and protein levels in the adrenal medulla (AM) and stellate ganglia (SG) of control and stressed mice. Both in AM and SG, single immobilization significantly increased TH and DBH mRNA and protein levels both in wild-type (WT) and CRH-KO mice. On the other hand, the stress-triggered increase in PNMT mRNA and protein levels seen in WT mice was absent in CRH-KO mice. DBH-KO mice are more sensitive to stress but survive a single 2 h restraint stress in a tube. The increase in TH mRNA levels induced by restraint stress in WT was not observed in DBH-KO mice. PNMT mRNA and especially PNMT protein levels were significantly elevated in AM of DBH-KO mice. In SG of DBH-KO mice, TH mRNA levels were not affected; however, PNMT gene expression was highly elevated. Thus, disruption of the DBH gene surprisingly blocks the stress-induced elevation of TH mRNA levels in AM but increases PNMT gene expression in both AM and SG. Our data indicate that adrenergic signaling is required for stress-induced increase in TH mRNA and that this signaling restrains stress-induced increase in PNMT mRNA. They also confirm that the HPA system plays a crucial role in the stress-induced regulation of PNMT gene expression.

Published
2008
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results