The pathogenetic mechanism in hematological malignancies

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The pathogenetic mechanism in hematological malignancies (en)
Испитивање патогенезе хематолошких малигнитета (sr)
Ispitivanje patogeneze hematoloških maligniteta (sr_RS)
Authors

Publications

Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms

Suboticki, Tijana; Ajtic, Olivera Mitrovic; Beleslin-Cokic, Bojana B.; Nienhold, Ronny; Diklić, Milos; Djikic, Dragoslava; Lekovic, Danijela; Bulat, Tanja M.; Marković, Dragana; Gotic, Mirjana; Noguchi, Constance T.; Schechter, Alan N.; Skoda, Radek C.; Cokic, Vladan P.

(2017)

TY  - JOUR
AU  - Suboticki, Tijana
AU  - Ajtic, Olivera Mitrovic
AU  - Beleslin-Cokic, Bojana B.
AU  - Nienhold, Ronny
AU  - Diklić, Milos
AU  - Djikic, Dragoslava
AU  - Lekovic, Danijela
AU  - Bulat, Tanja M.
AU  - Marković, Dragana
AU  - Gotic, Mirjana
AU  - Noguchi, Constance T.
AU  - Schechter, Alan N.
AU  - Skoda, Radek C.
AU  - Cokic, Vladan P.
PY  - 2017
UR  - http://vinar.vin.bg.ac.rs/handle/123456789/1395
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. (c) 2016 Wiley Periodicals, Inc.
T2  - Molecular Carcinogenesis
T1  - Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms
VL  - 56
IS  - 2
SP  - 567
EP  - 579
DO  - 10.1002/mc.22517
ER  - 
@article{
author = "Suboticki, Tijana and Ajtic, Olivera Mitrovic and Beleslin-Cokic, Bojana B. and Nienhold, Ronny and Diklić, Milos and Djikic, Dragoslava and Lekovic, Danijela and Bulat, Tanja M. and Marković, Dragana and Gotic, Mirjana and Noguchi, Constance T. and Schechter, Alan N. and Skoda, Radek C. and Cokic, Vladan P.",
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. (c) 2016 Wiley Periodicals, Inc.",
journal = "Molecular Carcinogenesis",
title = "Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms",
volume = "56",
number = "2",
pages = "567-579",
doi = "10.1002/mc.22517"
}
Suboticki, T., Ajtic, O. M., Beleslin-Cokic, B. B., Nienhold, R., Diklić, M., Djikic, D., Lekovic, D., Bulat, T. M., Marković, D., Gotic, M., Noguchi, C. T., Schechter, A. N., Skoda, R. C.,& Cokic, V. P.. (2017). Angiogenic factors are increased in circulating granulocytes and CD34(+) cells of myeloproliferative neoplasms. in Molecular Carcinogenesis, 56(2), 567-579.
https://doi.org/10.1002/mc.22517
Suboticki T, Ajtic OM, Beleslin-Cokic BB, Nienhold R, Diklić M, Djikic D, Lekovic D, Bulat TM, Marković D, Gotic M, Noguchi CT, Schechter AN, Skoda RC, Cokic VP. 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 .
Suboticki, Tijana, Ajtic, Olivera Mitrovic, Beleslin-Cokic, Bojana B., Nienhold, Ronny, Diklić, Milos, Djikic, Dragoslava, Lekovic, Danijela, Bulat, Tanja M., Marković, Dragana, Gotic, Mirjana, Noguchi, Constance T., Schechter, Alan N., Skoda, Radek C., Cokic, Vladan P., "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 . .
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Chronic psychological stress activates BMP4-dependent extramedullary erythropoiesis

Vignjevic, Sanja; Budec, Mirela; Marković, Dragana; Dikic, Dragoslava; Mitrovic, Olivera; Mojsilovic, Slavko; Vranješ-Đurić, Sanja; Koko, Vesna; Cokic, Bojana Beleslin; Cokic, Vladan; Jovcic, Gordana

(2014)

TY  - JOUR
AU  - Vignjevic, Sanja
AU  - Budec, Mirela
AU  - Marković, Dragana
AU  - Dikic, Dragoslava
AU  - Mitrovic, Olivera
AU  - Mojsilovic, Slavko
AU  - Vranješ-Đurić, Sanja
AU  - Koko, Vesna
AU  - Cokic, Bojana Beleslin
AU  - Cokic, Vladan
AU  - Jovcic, Gordana
PY  - 2014
UR  - http://vinar.vin.bg.ac.rs/handle/123456789/5818
AB  - Psychological stress affects different physiological processes including haematopoiesis. However, erythropoietic effects of chronic psychological stress remain largely unknown. The adult spleen contains a distinct microenvironment favourable for rapid expansion of erythroid progenitors in response to stressful stimuli, and emerging evidence suggests that inappropriate activation of stress erythropoiesis may predispose to leukaemic transformation. We used a mouse model to study the influence of chronic psychological stress on erythropoiesis in the spleen and to investigate potential mediators of observed effects. Adult mice were subjected to 2hrs daily restraint stress for 7 or 14 consecutive days. Our results showed that chronic exposure to restraint stress decreased the concentration of haemoglobin in the blood, elevated circulating levels of erythropoietin and corticosterone, and resulted in markedly increased number of erythroid progenitors and precursors in the spleen. Western blot analysis revealed significantly decreased expression of both erythropoietin receptor and glucocorticoid receptor in the spleen of restrained mice. Furthermore, chronic stress enhanced the expression of stem cell factor receptor in the red pulp. Moreover, chronically stressed animals exhibited significantly increased expression of bone morphogenetic protein 4 (BMP4) in the red pulp as well as substantially enhanced mRNA expression levels of its receptors in the spleen. These findings demonstrate for the first time that chronic psychological stress activates BMP4-dependent extramedullary erythropoiesis and leads to the prolonged activation of stress erythropoiesis pathways. Prolonged activation of these pathways along with an excessive production of immature erythroid cells may predispose chronically stressed subjects to a higher risk of leukaemic transformation.
T2  - Journal of Cellular and Molecular Medicine
T1  - Chronic psychological stress activates BMP4-dependent extramedullary erythropoiesis
VL  - 18
IS  - 1
SP  - 91
EP  - 103
DO  - 10.1111/jcmm.12167
ER  - 
@article{
author = "Vignjevic, Sanja and Budec, Mirela and Marković, Dragana and Dikic, Dragoslava and Mitrovic, Olivera and Mojsilovic, Slavko and Vranješ-Đurić, Sanja and Koko, Vesna and Cokic, Bojana Beleslin and Cokic, Vladan and Jovcic, Gordana",
year = "2014",
abstract = "Psychological stress affects different physiological processes including haematopoiesis. However, erythropoietic effects of chronic psychological stress remain largely unknown. The adult spleen contains a distinct microenvironment favourable for rapid expansion of erythroid progenitors in response to stressful stimuli, and emerging evidence suggests that inappropriate activation of stress erythropoiesis may predispose to leukaemic transformation. We used a mouse model to study the influence of chronic psychological stress on erythropoiesis in the spleen and to investigate potential mediators of observed effects. Adult mice were subjected to 2hrs daily restraint stress for 7 or 14 consecutive days. Our results showed that chronic exposure to restraint stress decreased the concentration of haemoglobin in the blood, elevated circulating levels of erythropoietin and corticosterone, and resulted in markedly increased number of erythroid progenitors and precursors in the spleen. Western blot analysis revealed significantly decreased expression of both erythropoietin receptor and glucocorticoid receptor in the spleen of restrained mice. Furthermore, chronic stress enhanced the expression of stem cell factor receptor in the red pulp. Moreover, chronically stressed animals exhibited significantly increased expression of bone morphogenetic protein 4 (BMP4) in the red pulp as well as substantially enhanced mRNA expression levels of its receptors in the spleen. These findings demonstrate for the first time that chronic psychological stress activates BMP4-dependent extramedullary erythropoiesis and leads to the prolonged activation of stress erythropoiesis pathways. Prolonged activation of these pathways along with an excessive production of immature erythroid cells may predispose chronically stressed subjects to a higher risk of leukaemic transformation.",
journal = "Journal of Cellular and Molecular Medicine",
title = "Chronic psychological stress activates BMP4-dependent extramedullary erythropoiesis",
volume = "18",
number = "1",
pages = "91-103",
doi = "10.1111/jcmm.12167"
}
Vignjevic, S., Budec, M., Marković, D., Dikic, D., Mitrovic, O., Mojsilovic, S., Vranješ-Đurić, S., Koko, V., Cokic, B. B., Cokic, V.,& Jovcic, G.. (2014). Chronic psychological stress activates BMP4-dependent extramedullary erythropoiesis. in Journal of Cellular and Molecular Medicine, 18(1), 91-103.
https://doi.org/10.1111/jcmm.12167
Vignjevic S, Budec M, Marković D, Dikic D, Mitrovic O, Mojsilovic S, Vranješ-Đurić S, Koko V, Cokic BB, Cokic V, Jovcic G. Chronic psychological stress activates BMP4-dependent extramedullary erythropoiesis. in Journal of Cellular and Molecular Medicine. 2014;18(1):91-103.
doi:10.1111/jcmm.12167 .
Vignjevic, Sanja, Budec, Mirela, Marković, Dragana, Dikic, Dragoslava, Mitrovic, Olivera, Mojsilovic, Slavko, Vranješ-Đurić, Sanja, Koko, Vesna, Cokic, Bojana Beleslin, Cokic, Vladan, Jovcic, Gordana, "Chronic psychological stress activates BMP4-dependent extramedullary erythropoiesis" in Journal of Cellular and Molecular Medicine, 18, no. 1 (2014):91-103,
https://doi.org/10.1111/jcmm.12167 . .
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Ethanol and nitric oxide modulate expression of glucocorticoid receptor in the rat adrenal cortex

Djikic, Dragoslava; Budec, Mirela; Vranješ-Đurić, Sanja; Todorović, Vera; Drndarević, Neda C.; Vignjevic, Sanja; Mitrovic, Olivera

(2012)

TY  - JOUR
AU  - Djikic, Dragoslava
AU  - Budec, Mirela
AU  - Vranješ-Đurić, Sanja
AU  - Todorović, Vera
AU  - Drndarević, Neda C.
AU  - Vignjevic, Sanja
AU  - Mitrovic, Olivera
PY  - 2012
UR  - http://vinar.vin.bg.ac.rs/handle/123456789/5130
AB  - Background: This study was performed to investigate expression and distribution of glucocorticoid receptor (GR) in the rat adrenal cortex, acute effect of ethanol on its expression and possible role of endogenous nitric oxide (NO) in this phenomenon. Methods: Adult female Wistar rats showing diestrus day 1 were treated with: a) ethanol (2 or 4 g/kg body weight (b.w.), ip), b) N-omega-nitro-L-arginine methyl ester (L-NAME), well-known competitive inhibitor of all isoforms of NO synthase (NOS), (30 mg/kg b.w., sc) followed by ethanol (4 g/kg, ip) 3 h later and c) L-NAME (30 mg/kg b.w., sc) followed by saline (ip) 3 h later. Untreated rats were used as controls. Adrenocortical expression of GR was estimated by immunohistochemistry. Results: Strong nuclear GR staining was observed throughout the cortex of control rats. Acute ethanol treatment significantly decreased the expression of GR in the zona fasciculata and zona reticularis. Blockade of NO formation had no influence on this effect of ethanol, whereas L-NAME itself induced significant decline in GR immunoreactivity. Conclusions: Obtained findings are the first to demonstrate localization and distribution of the GR throughout the rat adrenal cortex and to suggest that ethanol as well as endogenous NO may modulate adrenocortical expression of this steroid receptor.
T2  - Pharmacological Reports
T1  - Ethanol and nitric oxide modulate expression of glucocorticoid receptor in the rat adrenal cortex
VL  - 64
IS  - 4
SP  - 896
EP  - 901
DO  - 10.1016/S1734-1140(12)70884-8
ER  - 
@article{
author = "Djikic, Dragoslava and Budec, Mirela and Vranješ-Đurić, Sanja and Todorović, Vera and Drndarević, Neda C. and Vignjevic, Sanja and Mitrovic, Olivera",
year = "2012",
abstract = "Background: This study was performed to investigate expression and distribution of glucocorticoid receptor (GR) in the rat adrenal cortex, acute effect of ethanol on its expression and possible role of endogenous nitric oxide (NO) in this phenomenon. Methods: Adult female Wistar rats showing diestrus day 1 were treated with: a) ethanol (2 or 4 g/kg body weight (b.w.), ip), b) N-omega-nitro-L-arginine methyl ester (L-NAME), well-known competitive inhibitor of all isoforms of NO synthase (NOS), (30 mg/kg b.w., sc) followed by ethanol (4 g/kg, ip) 3 h later and c) L-NAME (30 mg/kg b.w., sc) followed by saline (ip) 3 h later. Untreated rats were used as controls. Adrenocortical expression of GR was estimated by immunohistochemistry. Results: Strong nuclear GR staining was observed throughout the cortex of control rats. Acute ethanol treatment significantly decreased the expression of GR in the zona fasciculata and zona reticularis. Blockade of NO formation had no influence on this effect of ethanol, whereas L-NAME itself induced significant decline in GR immunoreactivity. Conclusions: Obtained findings are the first to demonstrate localization and distribution of the GR throughout the rat adrenal cortex and to suggest that ethanol as well as endogenous NO may modulate adrenocortical expression of this steroid receptor.",
journal = "Pharmacological Reports",
title = "Ethanol and nitric oxide modulate expression of glucocorticoid receptor in the rat adrenal cortex",
volume = "64",
number = "4",
pages = "896-901",
doi = "10.1016/S1734-1140(12)70884-8"
}
Djikic, D., Budec, M., Vranješ-Đurić, S., Todorović, V., Drndarević, N. C., Vignjevic, S.,& Mitrovic, O.. (2012). Ethanol and nitric oxide modulate expression of glucocorticoid receptor in the rat adrenal cortex. in Pharmacological Reports, 64(4), 896-901.
https://doi.org/10.1016/S1734-1140(12)70884-8
Djikic D, Budec M, Vranješ-Đurić S, Todorović V, Drndarević NC, Vignjevic S, Mitrovic O. Ethanol and nitric oxide modulate expression of glucocorticoid receptor in the rat adrenal cortex. in Pharmacological Reports. 2012;64(4):896-901.
doi:10.1016/S1734-1140(12)70884-8 .
Djikic, Dragoslava, Budec, Mirela, Vranješ-Đurić, Sanja, Todorović, Vera, Drndarević, Neda C., Vignjevic, Sanja, Mitrovic, Olivera, "Ethanol and nitric oxide modulate expression of glucocorticoid receptor in the rat adrenal cortex" in Pharmacological Reports, 64, no. 4 (2012):896-901,
https://doi.org/10.1016/S1734-1140(12)70884-8 . .
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The Acute Effect of Ethanol on Adrenal Cortex in Female Rats-Possible Role of Nitric Oxide

Dikic, Dragoslava; Budec, Mirela; Vranješ-Đurić, Sanja; Koko, Vesna; Vignjevic, Sanja; Mitrovic, Olivera

(2011)

TY  - JOUR
AU  - Dikic, Dragoslava
AU  - Budec, Mirela
AU  - Vranješ-Đurić, Sanja
AU  - Koko, Vesna
AU  - Vignjevic, Sanja
AU  - Mitrovic, Olivera
PY  - 2011
UR  - http://vinar.vin.bg.ac.rs/handle/123456789/4457
AB  - Aims: The present study was designed to investigate a possible role of endogenous nitric oxide (NO) in the adrenal response to an acute alcohol administration in female rats. To this end, N(omega)-nitro-l-arginine-methyl ester (l-NAME), a competitive inhibitor of all isoforms of NO synthase, was used. Methods: Adult female Wistar rats showing diestrus Day 1 were treated with: (a) ethanol (2 or 4 g/kg, intraperitoneally); (b) l-NAME (30 or 50 mg/kg, subcutaneously) followed by either ethanol or saline 3 h later. Untreated and saline-injected rats were used as controls. The animals were killed 30 min after last injection. Adrenal cortex was analyzed morphometrically, and plasma levels of adrenocorticotropic hormone (ACTH) and serum concentrations of corticosterone were determined. Results: Acute ethanol treatment enhanced the levels of ACTH and corticosterone in a dose-dependent manner. Stereological analysis revealed that acute alcohol administration induced a significant increase in absolute volume of the cortex and the zona fasciculata (ZF). In addition, ethanol at a dose of 4 g/kg increased volume density and length of the capillaries in the ZF. However, other stereological parameters were unaffected by alcohol exposure. Pretreatment with both doses of l-NAME had no effect on ethanol-induced changes. Conclusion: Obtained findings indicate that acute ethanol treatment stimulates the activity of the adrenal cortex and that this effect is not mediated by endogenous NO in female rats under these experimental conditions.
T2  - Alcohol and Alcoholism
T1  - The Acute Effect of Ethanol on Adrenal Cortex in Female Rats-Possible Role of Nitric Oxide
VL  - 46
IS  - 5
SP  - 523
EP  - 528
DO  - 10.1093/alcalc/agr054
ER  - 
@article{
author = "Dikic, Dragoslava and Budec, Mirela and Vranješ-Đurić, Sanja and Koko, Vesna and Vignjevic, Sanja and Mitrovic, Olivera",
year = "2011",
abstract = "Aims: The present study was designed to investigate a possible role of endogenous nitric oxide (NO) in the adrenal response to an acute alcohol administration in female rats. To this end, N(omega)-nitro-l-arginine-methyl ester (l-NAME), a competitive inhibitor of all isoforms of NO synthase, was used. Methods: Adult female Wistar rats showing diestrus Day 1 were treated with: (a) ethanol (2 or 4 g/kg, intraperitoneally); (b) l-NAME (30 or 50 mg/kg, subcutaneously) followed by either ethanol or saline 3 h later. Untreated and saline-injected rats were used as controls. The animals were killed 30 min after last injection. Adrenal cortex was analyzed morphometrically, and plasma levels of adrenocorticotropic hormone (ACTH) and serum concentrations of corticosterone were determined. Results: Acute ethanol treatment enhanced the levels of ACTH and corticosterone in a dose-dependent manner. Stereological analysis revealed that acute alcohol administration induced a significant increase in absolute volume of the cortex and the zona fasciculata (ZF). In addition, ethanol at a dose of 4 g/kg increased volume density and length of the capillaries in the ZF. However, other stereological parameters were unaffected by alcohol exposure. Pretreatment with both doses of l-NAME had no effect on ethanol-induced changes. Conclusion: Obtained findings indicate that acute ethanol treatment stimulates the activity of the adrenal cortex and that this effect is not mediated by endogenous NO in female rats under these experimental conditions.",
journal = "Alcohol and Alcoholism",
title = "The Acute Effect of Ethanol on Adrenal Cortex in Female Rats-Possible Role of Nitric Oxide",
volume = "46",
number = "5",
pages = "523-528",
doi = "10.1093/alcalc/agr054"
}
Dikic, D., Budec, M., Vranješ-Đurić, S., Koko, V., Vignjevic, S.,& Mitrovic, O.. (2011). The Acute Effect of Ethanol on Adrenal Cortex in Female Rats-Possible Role of Nitric Oxide. in Alcohol and Alcoholism, 46(5), 523-528.
https://doi.org/10.1093/alcalc/agr054
Dikic D, Budec M, Vranješ-Đurić S, Koko V, Vignjevic S, Mitrovic O. The Acute Effect of Ethanol on Adrenal Cortex in Female Rats-Possible Role of Nitric Oxide. in Alcohol and Alcoholism. 2011;46(5):523-528.
doi:10.1093/alcalc/agr054 .
Dikic, Dragoslava, Budec, Mirela, Vranješ-Đurić, Sanja, Koko, Vesna, Vignjevic, Sanja, Mitrovic, Olivera, "The Acute Effect of Ethanol on Adrenal Cortex in Female Rats-Possible Role of Nitric Oxide" in Alcohol and Alcoholism, 46, no. 5 (2011):523-528,
https://doi.org/10.1093/alcalc/agr054 . .
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