TY  - JOUR
AU  - Nienhold, Ronny
AU  - Ashcroft, Peter
AU  - Zmajković, Jakub
AU  - Rai, Shivam
AU  - Rao, Tata Nageswara
AU  - Drexler, Beatrice
AU  - Meyer, Sara C.
AU  - Lundberg, Pontus
AU  - Passweg, Jakob R.
AU  - Leković, Danijela
AU  - Čokić, Vladan
AU  - Bonhoeffer, Sebastian
AU  - Skoda, Radek C.
PY  - 2020
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/1012
PB  - Amer Soc Hematology, Washington
T2  - Blood
T1  - MPN patients with low mutant JAK2 allele burden show late expansion restricted to erythroid and megakaryocytic lineages
EP  - 2595
IS  - 22
SP  - 2591
VL  - 136
DO  - 10.1182/blood.2019002943
ER  - 

@article{
author = "Nienhold, Ronny and Ashcroft, Peter and Zmajković, Jakub and Rai, Shivam and Rao, Tata Nageswara and Drexler, Beatrice and Meyer, Sara C. and Lundberg, Pontus and Passweg, Jakob R. and Leković, Danijela and Čokić, Vladan and Bonhoeffer, Sebastian and Skoda, Radek C.",
year = "2020",
publisher = "Amer Soc Hematology, Washington",
journal = "Blood",
title = "MPN patients with low mutant JAK2 allele burden show late expansion restricted to erythroid and megakaryocytic lineages",
pages = "2595-2591",
number = "22",
volume = "136",
doi = "10.1182/blood.2019002943"
}

Nienhold, R., Ashcroft, P., Zmajković, J., Rai, S., Rao, T. N., Drexler, B., Meyer, S. C., Lundberg, P., Passweg, J. R., Leković, D., Čokić, V., Bonhoeffer, S.,& Skoda, R. C.. (2020). MPN patients with low mutant JAK2 allele burden show late expansion restricted to erythroid and megakaryocytic lineages. in Blood
Amer Soc Hematology, Washington., 136(22), 2591-2595.
https://doi.org/10.1182/blood.2019002943

Nienhold R, Ashcroft P, Zmajković J, Rai S, Rao TN, Drexler B, Meyer SC, Lundberg P, Passweg JR, Leković D, Čokić V, Bonhoeffer S, Skoda RC. MPN patients with low mutant JAK2 allele burden show late expansion restricted to erythroid and megakaryocytic lineages. in Blood. 2020;136(22):2591-2595.
doi:10.1182/blood.2019002943 .

Nienhold, Ronny, Ashcroft, Peter, Zmajković, Jakub, Rai, Shivam, Rao, Tata Nageswara, Drexler, Beatrice, Meyer, Sara C., Lundberg, Pontus, Passweg, Jakob R., Leković, Danijela, Čokić, Vladan, Bonhoeffer, Sebastian, Skoda, Radek C., "MPN patients with low mutant JAK2 allele burden show late expansion restricted to erythroid and megakaryocytic lineages" in Blood, 136, no. 22 (2020):2591-2595,
https://doi.org/10.1182/blood.2019002943 . .

TY  - JOUR
AU  - Rao, Tata Nageswara
AU  - Hansen, Nils
AU  - Hilfiker, Julian
AU  - Rai, Shivam
AU  - Majewska, Julia-Magdalena
AU  - Leković, Danijela
AU  - Gezer, Deniz
AU  - Andina, Nicola
AU  - Galli, Serena
AU  - Cassel, Teresa
AU  - Geier, Florian
AU  - Delezie, Julien
AU  - Nienhold, Ronny
AU  - Hao-Shen, Hui
AU  - Beisel, Christian
AU  - Di Palma, Serena
AU  - Dimeloe, Sarah
AU  - Trebicka, Jonel
AU  - Wolf, Dominik
AU  - Gassmann, Max
AU  - Fan, Teresa W. -M.
AU  - Lane, Andrew N.
AU  - Handschin, Christoph
AU  - Dirnhofer, Stefan
AU  - Kroeger, Nicolaus
AU  - Hess, Christoph
AU  - Radimerski, Thomas
AU  - Koschmieder, Steffen
AU  - Čokić, Vladan
AU  - Skoda, Radek C.
PY  - 2019
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/919
AB  - Increased energy requirement and metabolic reprogramming are hallmarks of cancer cells. We show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2-driven myeloproliferative neoplasms (MPNs). We found that expression of mutant JAK2 augmented and subverted metabolic activity of MPN cells, resulting in systemic metabolic changes in vivo, including hypoglycemia, adipose tissue atrophy, and early mortality. Hypoglycemia in MPN mouse models correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation. Modulating nutrient supply through high-fat diet improved survival, whereas high-glucose diet augmented the MPN phenotype. Transcriptomic and metabolomic analyses identified numerous metabolic nodes in JAK2-mutant hematopoietic stem and progenitor cells that were altered in comparison with wild-type controls. We studied the consequences of elevated levels of Pfkfb3, a key regulatory enzyme of glycolysis, and found that pharmacological inhibition of Pfkfb3 with the small molecule 3PO reversed hypoglycemia and reduced hematopoietic manifestations of MPNs. These effects were additive with the JAK1/2 inhibitor ruxolitinib in vivo and in vitro. Inhibition of glycolysis by 3PO altered the redox homeostasis, leading to accumulation of reactive oxygen species and augmented apoptosis rate. Our findings reveal the contribution of metabolic alterations to the pathogenesis of MPNs and suggest that metabolic dependencies of mutant cells represent vulnerabilities that can be targeted for treating MPNs.
PB  - Amer Soc Hematology, Washington
T2  - Blood
T1  - JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms
EP  - 1846
IS  - 21
SP  - 1832
VL  - 134
DO  - 10.1182/blood.2019000162
ER  - 

@article{
author = "Rao, Tata Nageswara and Hansen, Nils and Hilfiker, Julian and Rai, Shivam and Majewska, Julia-Magdalena and Leković, Danijela and Gezer, Deniz and Andina, Nicola and Galli, Serena and Cassel, Teresa and Geier, Florian and Delezie, Julien and Nienhold, Ronny and Hao-Shen, Hui and Beisel, Christian and Di Palma, Serena and Dimeloe, Sarah and Trebicka, Jonel and Wolf, Dominik and Gassmann, Max and Fan, Teresa W. -M. and Lane, Andrew N. and Handschin, Christoph and Dirnhofer, Stefan and Kroeger, Nicolaus and Hess, Christoph and Radimerski, Thomas and Koschmieder, Steffen and Čokić, Vladan and Skoda, Radek C.",
year = "2019",
abstract = "Increased energy requirement and metabolic reprogramming are hallmarks of cancer cells. We show that metabolic alterations in hematopoietic cells are fundamental to the pathogenesis of mutant JAK2-driven myeloproliferative neoplasms (MPNs). We found that expression of mutant JAK2 augmented and subverted metabolic activity of MPN cells, resulting in systemic metabolic changes in vivo, including hypoglycemia, adipose tissue atrophy, and early mortality. Hypoglycemia in MPN mouse models correlated with hyperactive erythropoiesis and was due to a combination of elevated glycolysis and increased oxidative phosphorylation. Modulating nutrient supply through high-fat diet improved survival, whereas high-glucose diet augmented the MPN phenotype. Transcriptomic and metabolomic analyses identified numerous metabolic nodes in JAK2-mutant hematopoietic stem and progenitor cells that were altered in comparison with wild-type controls. We studied the consequences of elevated levels of Pfkfb3, a key regulatory enzyme of glycolysis, and found that pharmacological inhibition of Pfkfb3 with the small molecule 3PO reversed hypoglycemia and reduced hematopoietic manifestations of MPNs. These effects were additive with the JAK1/2 inhibitor ruxolitinib in vivo and in vitro. Inhibition of glycolysis by 3PO altered the redox homeostasis, leading to accumulation of reactive oxygen species and augmented apoptosis rate. Our findings reveal the contribution of metabolic alterations to the pathogenesis of MPNs and suggest that metabolic dependencies of mutant cells represent vulnerabilities that can be targeted for treating MPNs.",
publisher = "Amer Soc Hematology, Washington",
journal = "Blood",
title = "JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms",
pages = "1846-1832",
number = "21",
volume = "134",
doi = "10.1182/blood.2019000162"
}

Rao, T. N., Hansen, N., Hilfiker, J., Rai, S., Majewska, J., Leković, D., Gezer, D., Andina, N., Galli, S., Cassel, T., Geier, F., Delezie, J., Nienhold, R., Hao-Shen, H., Beisel, C., Di Palma, S., Dimeloe, S., Trebicka, J., Wolf, D., Gassmann, M., Fan, T. W. -M., Lane, A. N., Handschin, C., Dirnhofer, S., Kroeger, N., Hess, C., Radimerski, T., Koschmieder, S., Čokić, V.,& Skoda, R. C.. (2019). JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms. in Blood
Amer Soc Hematology, Washington., 134(21), 1832-1846.
https://doi.org/10.1182/blood.2019000162

Rao TN, Hansen N, Hilfiker J, Rai S, Majewska J, Leković D, Gezer D, Andina N, Galli S, Cassel T, Geier F, Delezie J, Nienhold R, Hao-Shen H, Beisel C, Di Palma S, Dimeloe S, Trebicka J, Wolf D, Gassmann M, Fan TW-, Lane AN, Handschin C, Dirnhofer S, Kroeger N, Hess C, Radimerski T, Koschmieder S, Čokić V, Skoda RC. JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms. in Blood. 2019;134(21):1832-1846.
doi:10.1182/blood.2019000162 .

Rao, Tata Nageswara, Hansen, Nils, Hilfiker, Julian, Rai, Shivam, Majewska, Julia-Magdalena, Leković, Danijela, Gezer, Deniz, Andina, Nicola, Galli, Serena, Cassel, Teresa, Geier, Florian, Delezie, Julien, Nienhold, Ronny, Hao-Shen, Hui, Beisel, Christian, Di Palma, Serena, Dimeloe, Sarah, Trebicka, Jonel, Wolf, Dominik, Gassmann, Max, Fan, Teresa W. -M., Lane, Andrew N., Handschin, Christoph, Dirnhofer, Stefan, Kroeger, Nicolaus, Hess, Christoph, Radimerski, Thomas, Koschmieder, Steffen, Čokić, Vladan, Skoda, Radek C., "JAK2-mutant hematopoietic cells display metabolic alterations that can be targeted to treat myeloproliferative neoplasms" in Blood, 134, no. 21 (2019):1832-1846,
https://doi.org/10.1182/blood.2019000162 . .

TY  - JOUR
AU  - Leković, Danijela
AU  - Gotić, Mirjana
AU  - Skoda, Radek C.
AU  - Beleslin-Čokić, Bojana
AU  - Milić, Nataša
AU  - Mitrović-Ajtić, Olivera
AU  - Nienhold, Ronny
AU  - Sefer, Dijana
AU  - Subotički, Tijana
AU  - Kovačić, Marijana
AU  - Marković, Dragana
AU  - Diklić, Miloš
AU  - Čokić, Vladan
PY  - 2017
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/804
AB  - Increased angiogenesis in BCR-ABL1 negative myeloproliferative neoplasms (MPNs) has been recognized, but its connection with clinical and molecular markers needs to be defined. The aims of study were to (1) assess bone marrow (BM) angiogenesis measured by microvessel density (MVD) using CD34 and CD105 antibodies; (2) analyze correlation of MVD with plasma angiogenic factors including vascular endothelial growth factor, basic fibroblast growth factor, and interleukin-8; (3) examine the association of MVD with clinicopathological and molecular markers. We examined 90 de novo MPN patients (30 polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET)) and 10 age-matched controls. MVD was analyzed by immunohistochemistry "hot spot" method, angiogenic factors by immunoassay and JAK2V617F, and CALR mutations by DNA sequencing and allelic PCR. MVD was significantly increased in MPNs compared to controls (PMF  gt  PV  gt  ET). Correlation between MVD and plasma angiogenic factors was found in MPNs. MVD was significantly increased in patients with JAK2V617F mutation and correlated with JAK2 mutant allele burden (CD34-MVD: rho = 0.491, p  lt  0.001; CD105-MVD: rho = 0.276, p = 0.02) but not with CALR mutation. MVD correlated with leukocyte count, serum lactate dehydrogenase, hepatomegaly, and splenomegaly. BM fibrosis was significantly associated with CD34-MVD, CD105-MVD, interleukin-8, and JAK2 mutant allele burden. JAK2 homozygote status had positive predictive value (100%) for BM fibrosis. Patients with prefibrotic PMF had significantly higher MVD than patients with ET, and we could recommend MVD to be additional histopathological marker to distinguish these two entities. This study also highlights the strong correlation of MVD with plasma angiogenic factors, JAK2 mutant allele burden, and BM fibrosis in MPNs.
PB  - Springer, New York
T2  - Annals of Hematology
T1  - Bone marrow microvessel density and plasma angiogenic factors in myeloproliferative neoplasms: clinicopathological and molecular correlations
EP  - 404
IS  - 3
SP  - 393
VL  - 96
DO  - 10.1007/s00277-016-2890-9
ER  - 

@article{
author = "Leković, Danijela and Gotić, Mirjana and Skoda, Radek C. and Beleslin-Čokić, Bojana and Milić, Nataša and Mitrović-Ajtić, Olivera and Nienhold, Ronny and Sefer, Dijana and Subotički, Tijana and Kovačić, Marijana and Marković, Dragana and Diklić, Miloš and Čokić, Vladan",
year = "2017",
abstract = "Increased angiogenesis in BCR-ABL1 negative myeloproliferative neoplasms (MPNs) has been recognized, but its connection with clinical and molecular markers needs to be defined. The aims of study were to (1) assess bone marrow (BM) angiogenesis measured by microvessel density (MVD) using CD34 and CD105 antibodies; (2) analyze correlation of MVD with plasma angiogenic factors including vascular endothelial growth factor, basic fibroblast growth factor, and interleukin-8; (3) examine the association of MVD with clinicopathological and molecular markers. We examined 90 de novo MPN patients (30 polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET)) and 10 age-matched controls. MVD was analyzed by immunohistochemistry "hot spot" method, angiogenic factors by immunoassay and JAK2V617F, and CALR mutations by DNA sequencing and allelic PCR. MVD was significantly increased in MPNs compared to controls (PMF  gt  PV  gt  ET). Correlation between MVD and plasma angiogenic factors was found in MPNs. MVD was significantly increased in patients with JAK2V617F mutation and correlated with JAK2 mutant allele burden (CD34-MVD: rho = 0.491, p  lt  0.001; CD105-MVD: rho = 0.276, p = 0.02) but not with CALR mutation. MVD correlated with leukocyte count, serum lactate dehydrogenase, hepatomegaly, and splenomegaly. BM fibrosis was significantly associated with CD34-MVD, CD105-MVD, interleukin-8, and JAK2 mutant allele burden. JAK2 homozygote status had positive predictive value (100%) for BM fibrosis. Patients with prefibrotic PMF had significantly higher MVD than patients with ET, and we could recommend MVD to be additional histopathological marker to distinguish these two entities. This study also highlights the strong correlation of MVD with plasma angiogenic factors, JAK2 mutant allele burden, and BM fibrosis in MPNs.",
publisher = "Springer, New York",
journal = "Annals of Hematology",
title = "Bone marrow microvessel density and plasma angiogenic factors in myeloproliferative neoplasms: clinicopathological and molecular correlations",
pages = "404-393",
number = "3",
volume = "96",
doi = "10.1007/s00277-016-2890-9"
}

Leković, D., Gotić, M., Skoda, R. C., Beleslin-Čokić, B., Milić, N., Mitrović-Ajtić, O., Nienhold, R., Sefer, D., Subotički, T., Kovačić, M., Marković, D., Diklić, M.,& Čokić, V.. (2017). Bone marrow microvessel density and plasma angiogenic factors in myeloproliferative neoplasms: clinicopathological and molecular correlations. in Annals of Hematology
Springer, New York., 96(3), 393-404.
https://doi.org/10.1007/s00277-016-2890-9

Leković D, Gotić M, Skoda RC, Beleslin-Čokić B, Milić N, Mitrović-Ajtić O, Nienhold R, Sefer D, Subotički T, Kovačić M, Marković D, Diklić M, Čokić V. Bone marrow microvessel density and plasma angiogenic factors in myeloproliferative neoplasms: clinicopathological and molecular correlations. in Annals of Hematology. 2017;96(3):393-404.
doi:10.1007/s00277-016-2890-9 .

Leković, Danijela, Gotić, Mirjana, Skoda, Radek C., Beleslin-Čokić, Bojana, Milić, Nataša, Mitrović-Ajtić, Olivera, Nienhold, Ronny, Sefer, Dijana, Subotički, Tijana, Kovačić, Marijana, Marković, Dragana, Diklić, Miloš, Čokić, Vladan, "Bone marrow microvessel density and plasma angiogenic factors in myeloproliferative neoplasms: clinicopathological and molecular correlations" in Annals of Hematology, 96, no. 3 (2017):393-404,
https://doi.org/10.1007/s00277-016-2890-9 . .

TY  - JOUR
AU  - Subotički, Tijana
AU  - Mitrović-Ajtić, Olivera
AU  - Beleslin-Čokić, Bojana
AU  - Nienhold, Ronny
AU  - Diklić, Miloš
AU  - Đikić, Dragoslava
AU  - Leković, Danijela
AU  - Bulat, Tanja
AU  - Marković, Dragana
AU  - Gotić, Mirjana
AU  - Noguchi, Constance T.
AU  - Schechter, Alan N.
AU  - Skoda, Radek C.
AU  - Čokić, Vladan
PY  - 2017
UR  - http://rimi.imi.bg.ac.rs/handle/123456789/807
AB  - It has been shown that angiogenesis and inflammation play an important role in development of most hematological malignancies including the myeloproliferative neoplasm (MPN). The aim of this study was to investigate and correlate the levels of key angiogenic molecules such as hypoxia-inducible factor-1 (HIF-1), vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) in peripheral blood and bone marrow cells of MPN patients, along with JAK2V617F mutation allele burden and effects of therapy. HIF-1 and VEGF gene expression were decreased, while eNOS mRNA levels were increased in granulocytes of MPN patients. Furthermore, positively correlated and increased VEGF and eNOS protein levels were in negative correlation with HIF-1 levels in granulocytes of MPN patients. According to immunoblotting, the generally augmented angiogenic factors demonstrated JAK2V617F allele burden dependence only in granulocytes of PMF. The angiogenic factors were largely reduced after hydroxyurea therapy in granulocytes of MPN patients. Levels of eNOS protein expression were stimulated by Calreticulin mutations in granulocytes of essential thrombocythemia. Immunocytochemical analyses of CD34(+) cells showed a more pronounced enhancement of angiogenic factors than in granulocytes. Increased gene expression linked to the proinflammatory TGF and MAPK signaling pathways were detected in CD34(+) cells of MPN patients. In conclusion, the angiogenesis is increased in several cell types of MPN patients supported by the transcriptional activation of inflammation-related target genes, and is not limited to bone marrow stroma cells. It also appears that some of the benefit of hydroxyurea therapy of the MPN is mediated by effects on angiogenic factors.
PB  - Wiley-Blackwell, Hoboken
T2  - Molecular Carcinogenesis
T1  - Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms
EP  - 579
IS  - 2
SP  - 567
VL  - 56
DO  - 10.1002/mc.22517
ER  - 

@article{
author = "Subotički, Tijana and Mitrović-Ajtić, Olivera and Beleslin-Čokić, Bojana and Nienhold, Ronny and Diklić, Miloš and Đikić, Dragoslava and Leković, Danijela and Bulat, Tanja and Marković, Dragana and Gotić, Mirjana and Noguchi, Constance T. and Schechter, Alan N. and Skoda, Radek C. and Čokić, Vladan",
year = "2017",
abstract = "It has been shown that angiogenesis and inflammation play an important role in development of most hematological malignancies including the myeloproliferative neoplasm (MPN). The aim of this study was to investigate and correlate the levels of key angiogenic molecules such as hypoxia-inducible factor-1 (HIF-1), vascular endothelial growth factor (VEGF) and endothelial nitric oxide synthase (eNOS) in peripheral blood and bone marrow cells of MPN patients, along with JAK2V617F mutation allele burden and effects of therapy. HIF-1 and VEGF gene expression were decreased, while eNOS mRNA levels were increased in granulocytes of MPN patients. Furthermore, positively correlated and increased VEGF and eNOS protein levels were in negative correlation with HIF-1 levels in granulocytes of MPN patients. According to immunoblotting, the generally augmented angiogenic factors demonstrated JAK2V617F allele burden dependence only in granulocytes of PMF. The angiogenic factors were largely reduced after hydroxyurea therapy in granulocytes of MPN patients. Levels of eNOS protein expression were stimulated by Calreticulin mutations in granulocytes of essential thrombocythemia. Immunocytochemical analyses of CD34(+) cells showed a more pronounced enhancement of angiogenic factors than in granulocytes. Increased gene expression linked to the proinflammatory TGF and MAPK signaling pathways were detected in CD34(+) cells of MPN patients. In conclusion, the angiogenesis is increased in several cell types of MPN patients supported by the transcriptional activation of inflammation-related target genes, and is not limited to bone marrow stroma cells. It also appears that some of the benefit of hydroxyurea therapy of the MPN is mediated by effects on angiogenic factors.",
publisher = "Wiley-Blackwell, Hoboken",
journal = "Molecular Carcinogenesis",
title = "Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms",
pages = "579-567",
number = "2",
volume = "56",
doi = "10.1002/mc.22517"
}

Subotički, T., Mitrović-Ajtić, O., Beleslin-Čokić, B., Nienhold, R., Diklić, M., Đikić, D., Leković, D., Bulat, T., Marković, D., Gotić, M., Noguchi, C. T., Schechter, A. N., Skoda, R. C.,& Čokić, V.. (2017). Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms. in Molecular Carcinogenesis
Wiley-Blackwell, Hoboken., 56(2), 567-579.
https://doi.org/10.1002/mc.22517

Subotički T, Mitrović-Ajtić O, Beleslin-Čokić B, Nienhold R, Diklić M, Đikić D, Leković D, Bulat T, Marković D, Gotić M, Noguchi CT, Schechter AN, Skoda RC, Čokić V. Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms. in Molecular Carcinogenesis. 2017;56(2):567-579.
doi:10.1002/mc.22517 .

Subotički, Tijana, Mitrović-Ajtić, Olivera, Beleslin-Čokić, Bojana, 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, "Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms" in Molecular Carcinogenesis, 56, no. 2 (2017):567-579,
https://doi.org/10.1002/mc.22517 . .