Erythropoietin (EPO) is a hormone that is essential for the maturation of erythroid progenitors in the bone marrow. It acts through the binding to the erythropoietin receptor (EPOR), which is present on the surface of erythroid cells in the form of a homodimer. Signaling through the EPO-EPOR axis includes activation of several signaling pathways that drive proliferation and differentiation of haematopoietic cells and provide protection against apoptosis.
Erythrocytosis is blood disorder characterized by an increased mass of erythrocytes, hematocrit (Ht) and hemoglobin (Hb). It is caused by an inherited or acquired mutations or as a compensatory mechanism in some chronical disorders. Polycythemia vera (PV) is the most common acquired erythrocytosis caused by mutations in Janus kinase 2 (JAK2). Familial erythrocytosis (FE) is a rare congenital disorder with different genetic background, including variations in EPO and EPOR.
The research involves three research topics:
1. Genetic background of erythrocytosis in Slovenia (GenEry).
2. Pleiotropic effects of erythropoietin (PE-EPO: continuation of J3-0124 ).
3. The influence of cannabinoid receptors on the outcome of breast cancer treatment (CB-BCa).
⇒ Link to a current project page: L3-9279
Past and Present Research Projects:
- L3-9279 Genetic basis of erythrocytosis in Slovenia; applied national research project (N. Debeljak), 1/7/2018 – 30/6/2021); Erythrocytosis .
- National research program P1-0390 Functional Genomics and Biotechnology for Health; R. Komel, 1/1/2015 – 30/6/2017 / D. Rozman, 1/1/2015 – 31/12/2020 (previously P1-0104; 2009-2014, R. Komel); A/ Molecular and Cellular Understanding of Selected Complex Multifactorial Disorders: WP1c – Molecular roots of carcinogenesis (N. Debeljak); P1-0390 .
- J3―0124 Influence of recombinant human erythropoietin on gene expression and signal transduction in breast cancer; basic national research project (N. Debeljak), 1/2/2008―30/1/2011; J3-0124.
- Z3-9403 Molecular mechanism of action of the recombinant human erythropoietin on cancerous cells, post-doc research project (S. Berne) 1/1/2007 – 31/12/2008; Z3-9403 .
- Z1-4286 Erythropoietin (Epo) signaling pathway and the mechanism of signal transduction to c-myc; post-doc research project to N. Debeljak (R.Komel), 1/7/2002 – 30/6/2004; Z1-4286 .
Clinical partners:
- University Clinical Center Ljubljana (UKC), Clinical Department of Haematology and Specialized Haematology Laboratory (prof. Dr. Irena Preložnik Zupan, M.D., Dr. Saša Anžej Doma, M.D., Dr. Matjaž Sever, M.D., Dr. Tadej Pajič, Dr. Martina Fink, Dr. Helena Podgornik)
- Institute of Oncology Ljubljana (OI) (Dr. Simona Borštnar, M.D., Dr. Barabara Gazič, M.D., Prof. Gregor Serša)
- University Clinical Centre Ljubljana (UKC), Institute of Clinical Chemistry and Biochemistry (KIKKB) (Prof. Joško Osredkar)
Collaborating research/faculty institutes:
- Faculty of Medicine UL, Centre for Functional Genomics and Bio-Chips (CFGBC) (Prof. Damjana Rozman, Dr. Tadeja Režen)
- Faculty of Medicine UL, Institute for Biostatistics and Medical Informatics (IBMI) and ELIXIR-SI (Dr. Polonca Ferk, Dr. Brane Leskošek)
- Faculty of Medicine UL, Institute of cell biology (Prof. Peter Veranič)
- Biotechnical Faculty UL, Department of Animal Science (Prof. Tanja Kunej)
- National Institute of Biology (NIB), Department of Genetic Toxicology and Cancer Biology (prof. Tamara Lah Turnšek)
- Jozef Stefan Institute, Department of Molecular and Biomedical Sciences (Dr. Toni Petan)
Collaborating companies:
- Kemomed Ltd. (Tatjana Marčac Grahek)
International collaboration:
- Harward Medical School, Boston, USA (Prof. A. J. Sytkowski, M.D.).
- J. Šafárik University, Faculty of Sciences, Košice, Slovakia (Prof. Peter Solar)
- Institute for Medical Research, Beograd, Srbia (Prof. Vladan Čokić, M.D.)
- Hospital Dubrava, Zagreb, Croatia (Dr. Rajko Kušec, M.D.)
Researchers involved:
| Researcher | Position |
| Nataša Debeljak | Project Leader, P.I. |
| Aleša Kristan | PhD student, JR |
| Dubravka Germ | Technical assistant |
| *** | *** |
| Radovan Komel | MCMB Leader |
| Petra Hudler | Senior Researcher |
Former group members:
| Sandra Ropret | PostDoc Researcher |
| Jernej Gašperšič | PostDoc Researcher |
| Luka Dobovišek | M.D., PhD student |
| Klementina Fun Tacer | PostDoc Researcher |
| Sabina Berne | PostDoc Researcher |
| Nina Trošt | PhD student |
| Klemen Španinger | PhD student |
| Barbora Feckova | PhD student from Slovakia |
| Lena Kurtikova | PhD student from Slovakia |
| Patricia Kimakova | PhD student from Slovakia |
Education:
| Student | Thesis | Title | Year | Supervisor(s) | |
| Laura Albreht | MSc | Analysis of genetic variability ofBPGM in familial erythrocytosis. | 2019 |
Nataša Debeljak Tanja Kunej |
|
| Ida Hramus | MSc | Analysis of genetic variability of HBA1 and HBA2 in familial erythrocytosis. | 2019 |
Nataša Debeljak Tanja Kunej |
|
| Nina Rupar | MSc | Analysis of genetic variability of EGLN1 in familial erythrocytosis. | 2019 |
Nataša Debeljak Tanja Kunej |
|
| Ana Marentič | MSc | Analysis of genetic variability of HBB in familial erythrocytosis. | 2019 |
Nataša Debeljak Tanja Kunej |
|
| Fran Kristanovič | MSc | Characterization of cannabinoid receptors in breast cancer cell lines. | 2019 | Nataša Debeljak | |
| Patrik Levačić | BSc | Selection of antibodies for quantitative determination of cannabinoid receptors in breast cancer cell lines. | 2019 | Nataša Debeljak | |
| Janja Murn | BSc | Optimisation of a Dot blot method for determination of cannabinoids and estrogen receptors in breast cancer cell lines. | 2019 | Nataša Debeljak | |
| Tinkara Prijatelj | MSc | Analysis of the erythropoietin gene variability in familial erythrocytosis. | 2018 | Nataša Debeljak | |
| Iva Mencin | MSc | Analysis of tumor-suppressor VHL gene variations in familial erythrocytosis. | 2018 |
Nataša Debeljak Tanja Kunej |
|
| Aleša Kristan | MSc | Analysis of HIF2α gene variations in family erythrocytosis. | 2018 |
Nataša Debeljak Tanja Kunej |
|
| Danijela Vočanec | MSc | Analysis of erythropoietin receptor gene variations in patients with familial erythrocytosis. | 2018 |
Nataša Debeljak Tanja Kunej |
|
| Mateja Cigoj | MSc | Optimisation of immunodetection for erythropoietin and estrogen receptors in breast cancer cell lines. | 2018 | Nataša Debeljak | |
| Tinkara Šilc | MSc | Analysis of erythropoietin gene variations in patients with familial erythrocytosis. | 2017 |
Nataša Debeljak Tanja Kunej |
|
| Lucija Vermiglio, Anja Kopitar and Anja Solarovič | Prešern award | Genetic background of erythrocytosis in Slovenia. | 2017 |
Nataša Debeljak Irena Preložnik Zupan |
|
| Katja Čop | BSc | Selection of normalization method for detection of erythropoietin and estrogen receptors in breast cancer cell lines. | 2017 | Nataša Debeljak | |
| Blaž Lebar | BSc | Characterization of erythropoietin receptor protein with far-western and double transfer. | 2017 | Nataša Debeljak | |
| Urška Pevec (Kotnik) | MSc | The role of Erythropoietin receptor in Tamoxifen resistance. | 2017 | Nataša Debeljak | |
| Sara Košenina | BSc | Characterization of erythropoietin and estrogen receptor proteins in breast cancer cell lines. | 2015 | Nataša Debeljak | |
| Tine Prolič Kalinšek and Gašper Rizinger | Prešern award | Analysis of link between erythropoietin receptors expression and resistance to tamoxifen in a model breast cancer cell lines. | 2014 | Nataša Debeljak | |
| Nina Trošt | PhD | The effect of recombinant human erythropoietin on the growth and survivale of breast cancer cells and their responsivenes to cisplatin and tamoxifen. | 2013 | Nataša Debeljak | |
| Anita Lokar | MSc | Impact of biathlon training intensity on the modification of erythropoietin isoforms and haematological parameters. | 2013 |
J. Osredkar K. Španinger |
|
| Maja Peterle | MSc | Determination of erythropoietin in alpinists exposed to diverse altitudes, using isoelectric focusing | 2013 |
J. Osredkar Nataša Debeljak |
|
| Tina Stepišnik | MSc | Comparison of expression of different erythropoietin receptor forms in tumor and normal breast cell lines after acute and chronic erythropoietin treatment | 2012 | Sabina Berne | |
| Klemen Španinger | PhD | Recombinant human erythropoietin: analysis of the total erythropoietin with isoelectric focusing in cancer patients and the molecular mechanisms of neuroprotection in cell lines. | 2011 |
Nataša Debeljak Arthur E. Sytkowski |
Selected publications:
- Kristan A., Gašperšič J., Režen T., Kunej T., Količ R., Vuga A., Fink M., Žula Š., Anžej Doma S., Preložnik-Zupan I., Pajič T., Podgornik H., Debeljak N. (2021): Genetic analysis of 39 erythrocytosis and hereditary hemochromatosis-associated genes in the Slovenian family with idiopathic erythrocytosis. Journal of Clinical Laboratory Analysis xx; https://onlinelibrary.wiley.com/doi/epdf/10.1002/jcla.23715, doi: 10.1002/jcla.23715.
- Dobovišek L. et al. (2020): Cannabinoids and Hormone Receptor-Positive Breast Cancer Treatment (Review). Cancers 12(3): 525-536; doi: 10.3390/cancers12030525.
- Kristan A., Debeljak N., Kunej T. (2019): Genetic variability of hypoxia-inducible factor alpha (HIFA) genes in familial erythrocytosis : analysis of the literature and genome databases (Review). European Journal of Haematology; doi: 10.1111/ejh.13304.
- Fecková B. et al. (2019): Methylation of the first exon in the erythropoietin receptor gene does not correlate with its mRNA and protein level in cancer cells. BMC Genetics 20: 1-9; doi: 10.1186/s 12863-018-0706-8.
- Vočanec D. et al. (2019): Genetic variants of erythropoietin (EPO) and EPO receptor genes in familial erythrocytosis. Int J Lab Hematol. 41(2):162-167; doi: 10.1111/ijlh.12949; https://onlinelibrary.wiley.com/doi/full/10.1111/ijlh.12949.
- Debeljak N. et al. (2019): Characterization of erythrocytosis and a proposed diagnostic algorithm in Slovenia. Zd. Vest. 88(5-6):263-275; https://doi.org/10.6016/ZdravVestn.2880.
- Kimáková P. et. al. (2017): Erythropoietin and Its Angiogenic Activity. J. Mol. Sci. 18: 1519; doi: 10.3390/ijms18071519.
- Fecková B. et al. (2019): Methylation of the first exon in the erythropoietin receptor gene does not correlate with its mRNA and protein level in cancer cells. BMC Genet. 20(1):1; doi: 10.1186/s12863-018-0706-8.
- Ilkovičová L. et al. (2017): Overexpression of the erythropoietin receptor in RAMA 37 breast cancer cells alters cell growth and sensitivity to tamoxifen. Int. J. Oncol. 51:737-746; doi: 10.3892/ijo.2017.4061.
- Debeljak N. et al. (2014): Erythropoietin and Cancer: The unintended consequences of anemia correction. Front. Immunol. 5: 563, eCollection 2014; doi: 10.3389/fimmu.2014.00563.
- Trošt N. et al. (2013): Recombinant human erythropoietin effects proliferation and expression profile of MCF-7 breast cancer cell line. Radiol. Oncol. 47(4): 382–389; doi: 10.2478/raon-2013-0056.
- Trošt N. et al. (2013): Correlation between erythropoietin receptor(s) and estrogen and progesterone receptor expression in different breast cancer cell lines. Int. J. Mol. Med. 31(3): 717-725; doi: 10.3892/ijmm.2013.1231.
- Trošt N. et al. (2012): Contrasting effect of recombinant human erythropoietin on breast cancer cell response to cisplatin induced cytotoxicity. Radiol. Oncol. 46(3): 213-25; doi: 10.2478/v10019-012-0037-8.
- Debeljak N. and Sythowski A.J. (2012): Erythropoietin and erythropoiesis stimulating agents. Drug Test. Anal 4(11): 805-812; doi: 10.1002/dta.1341.
- Španinger K. et al. (2011): Isoelectric focusing profiles of erythropoietin in cancer patient during chemotherapy and darbepoetin treatment: case report. Acta Chim. Slov. 58(1): 139-143; https://www.ncbi.nlm.nih.gov/pubmed/24061954.
- Debeljak N. and Sythowski A.J. (2008): Erythropoetin: new approaches to improved molecular designs and therapeutic alternatives. Curr. Pharm. Design 14(13): 1302-1310; https://www.ncbi.nlm.nih.gov/pubmed/18537654.
- Debeljak N. and Sythowski A.J. (2007): EpoR. Nature [Online ed.], vol. 425, pp. [1-11]; http://www.signaling-gateway.org/molecule/query?afcsid=A000863&type=abstract.