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The Department of Haematology, of the University of Ioannina Medical School, has a strong research activity. This is evidenced by the increasing number of scientific papers, which are published in international peer reviewed medical journals and by presentations in national and international medical conferences. Over the last few years, our research has been focused on the study of the pathophysiological mechanisms that underlie blood cancers and in particular epigenetic modifications.

Cancer is principally a genetic disease with various genetic abnormalities, such as deletions, translocations and mutations, contributing to the malignant phenotype. Over the last two decades though, accumulating evidence suggests that cancer has both genetic and epigenetic abnormalities. Epigenetics refers to the study of mitotically and/or meiotically heritable changes in gene expression that occur without changes in the DNA sequence. These changes are potentially reversible and contribute to the phenotypic variation. Epigenetic modifications allow the cell to selectively express only this part of the genome that is needed for the function of the specific tissue the cell belongs to. Main examples of such changes are DNA methylation and histone modification, both of which serve to regulate gene expression without altering the underlying DNA sequence. These changes may remain through cell divisions for the remainder of the cell's life and may also last for multiple generations. DNA methylation is an important epigenetic modification that has been associated with carcinogenesis mainly due to silencing of tumour suppressor genes. In this setting, we have studied the DNA methylation status of several potential tumor suppressor genes in various blood cancers, such as acute myelogenous leukemia, myelodysplastic syndromes and multiple myeloma.

The study of epigenetic modifications in patients with haematological neoplasias is of high importance since they respond to the available epigenetic modifiers such as hypomethylating agents and histone deacetylase inhibitors.

   
Schematic diagram illustrating euchromatin and heterochromatin.
Heterochromatin on the left is characterized by DNA methylation and deacetylated histones, is condensed and inaccesible to transcription factors. On the contrary, euchromatin on the right is in a loose form and transcriptionally active; DNA is unmethylated and histone tails acetylated.
Adapted by E. Hatzimichael, L. Benetatos, E. Briasoulis, Haema 2011, 2: 2. 169-176 Apr-Jun

Recent publications
  1. E. Katodritou, C. Vadikolia, C. Lalagianni, M. Kotsopoulou, G. Papageorgiou, M. C. Kyrtsonis, P. Matsouka, N. Giannakoulas, D. Kyriakou, G. Karras, N. Anagnostopoulos, E. Michali, E. Briasoulis, E. Hatzimichael, E. Spanoudakis, P. Zikos, A. Tsakiridou, K. Tsionos, K. Anargyrou, A. Symeonidis, A. Maniatis, E. Terpos, "Real-world" data on the efficacy and safety of lenalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma who were treated according to the standard clinical practice: a study of the Greek Myeloma Study Group. Annals of hematology 93, 129-139 (2014).

  2. M. A. Dimopoulos, S. Delimpasi, E. Katodritou, A. Vassou, M. C. Kyrtsonis, P. Repousis, Z. Kartasis, A. Parcharidou, M. Michael, E. Michalis, D. Gika, A. Symeonidis, A. Pouli, K. Konstantopoulos, E. Terpos, E. Kastritis, Significant improvement in the survival of patients with multiple myeloma presenting with severe renal impairment after the introduction of novel agents. Annals of oncology 25, 195-200 (2014).

  3. L. Benetatos, G. Vartholomatos, E. Hatzimichael, Polycomb group proteins and MYC: the cancer connection. Cellular and molecular life sciences : CMLS 71, 257-269 (2014).

  4. A. G. Tzakos, E. Briasoulis, T. Thalhammer, W. Jager, V. Apostolopoulos, Novel oncology therapeutics: targeted drug delivery for cancer. Journal of drug delivery 2013, 918304 (2013).

  5. N. Syed, J. Langer, K. Janczar, P. Singh, C. Lo Nigro, L. Lattanzio, H. M. Coley, E. Hatzimichael, J. Bomalaski, P. Szlosarek, M. Awad, K. O'Neil, F. Roncaroli, T. Crook, Epigenetic status of argininosuccinate synthetase and argininosuccinate lyase modulates autophagy and cell death in glioblastoma. Cell death & disease 4, e458 (2013).

  6. A. Makis, A. Challa, E. Hatzimichael, E. Briasoulis, A. Siamopoulou, N. Chaliasos, Adipocytokines are related to haemolytic and inflammatory biomarkers in sickle cell beta thalassaemia. British journal of haematology 163, 142-144 (2013).

  7. C. Lo Nigro, H. Wang, A. McHugh, L. Lattanzio, R. Matin, C. Harwood, N. Syed, E. Hatzimichael, E. Briasoulis, M. Merlano, A. Evans, A. Thompson, I. Leigh, C. Fleming, G. J. Inman, C. Proby, T. Crook, Methylated tissue factor pathway inhibitor 2 (TFPI2) DNA in serum is a biomarker of metastatic melanoma. The Journal of investigative dermatology 133, 1278-1285 (2013).

  8. E. Hatzimichael, S. Murray, E. Briasoulis, Absence of BRAF exon 15 mutations in multiple myeloma and Waldenstrom's macroglobulinemia questions its validity as a therapeutic target in plasma cell neoplasias. American journal of blood research 3, 181-185 (2013).

  9. E. Hatzimichael, G. Georgiou, L. Benetatos, E. Briasoulis, Gene mutations and molecularly targeted therapies in acute myeloid leukemia. American journal of blood research 3, 29-51 (2013).

  10. E. Hatzimichael, T. Crook, Cancer epigenetics: new therapies and new challenges. Journal of drug delivery 2013, 529312 (2013).

  11. E. Hatzimichael, E. Briasoulis, Metronomic chemotherapy beyond misconceptions. Haematologica 98, e145 (2013).

  12. G. K. Georgiou, M. Igglezou, I. Sainis, K. Vareli, H. Batsis, E. Briasoulis, M. Fatouros, Impact of breast cancer surgery on angiogenesis circulating biomarkers: a prospective longitudinal study. World journal of surgical oncology 11, 213 (2013).

  13. M. Froudarakis, E. Hatzimichael, L. Kyriazopoulou, K. Lagos, P. Pappas, A. G. Tzakos, V. Karavasilis, D. Daliani, C. Papandreou, E. Briasoulis, Revisiting bleomycin from pathophysiology to safe clinical use. Critical reviews in oncology/hematology 87, 90-100 (2013).

  14. G. Dranitsaris, K. Dorward, E. Hatzimichael, E. Amir, Clinical trial design in biosimilar drug development. Investigational new drugs 31, 479-487 (2013).

  15. V. Buxhofer-Ausch, L. Secky, K. Wlcek, M. Svoboda, V. Kounnis, E. Briasoulis, A. G. Tzakos, W. Jaeger, T. Thalhammer, Tumor-specific expression of organic anion-transporting polypeptides: transporters as novel targets for cancer therapy. Journal of drug delivery 2013, 863539 (2013).

  16. E. Briasoulis, G. Aravantinos, G. Kouvatseas, P. Pappas, E. Biziota, I. Sainis, T. Makatsoris, I. Varthalitis, I. Xanthakis, A. Vassias, G. Klouvas, I. Boukovinas, G. Fountzilas, K. N. Syrigos, H. Kalofonos, E. Samantas, Dose selection trial of metronomic oral vinorelbine monotherapy in patients with metastatic cancer: a hellenic cooperative oncology group clinical translational study. BMC cancer 13, 263 (2013).

  17. L. Benetatos, E. Voulgaris, G. Vartholomatos, E. Hatzimichael, Non-coding RNAs and EZH2 interactions in cancer: long and short tales from the transcriptome. International journal of cancer. Journal international du cancer 133, 267-274 (2013).

  18. L. Benetatos, E. Hatzimichael, E. Londin, G. Vartholomatos, P. Loher, I. Rigoutsos, E. Briasoulis, The microRNAs within the DLK1-DIO3 genomic region: involvement in disease pathogenesis. Cellular and molecular life sciences : CMLS 70, 795-814 (2013).

  19. Hatzimichael E, Georgiou G, Benetatos L, Briasoulis E. Gene mutations and molecularly targeted therapies in acute myeloid leukemia. Am J Blood Res. 2013;3(1):29-51. Epub 2013 Jan 17

  20. Froudarakis M, Hatzimichael E, Kyriazopoulou L, Lagos K, Pappas P, Tzakos AG, Karavasilis V, Daliani D, Papandreou C, Briasoulis E. Revisiting bleomycin from pathophysiology to safe clinical use. Crit Rev Oncol Hematol. 2013; Jan 9

  21. Dranitsaris G, Dorward K, Hatzimichael E, Amir E. Clinical trial design in biosimilar drug development. Invest New Drugs 2012 Nov 17. [Epub ahead of print]

  22. Benetatos L, Voulgaris E, Vartholomatos G, Hatzimichael E.Int J Cancer. Non coding RNAs and EZH2 interactions in cancer: Long and short tales from the transcriptome. 2012 Sep 24. doi: 10.1002/ijc.27859. [Epub ahead of print] PMID: 23001607 [PubMed - as supplied by publisher]

  23. Hatzimichael E, Lo Nigro C, Lattanzio L, Syed N, Shah R, Dasoula A, Janczar K, Vivenza D, Monteverde M, Merlano M, Papoudou-Bai A, Bai M, Schmid P, Stebbing J, Bower M, Dyer MJ, Karran LE, Elguetakarstegl C, Farrell PJ, Thompson A, Briasoulis E, Crook T. The collagen prolyl hydroxylases are novel transcriptionally silenced genes in lymphoma. Br J Cancer. 2012 Sep 6.

  24. Benetatos L, Hatzimichael E, Londin E, Vartholomatos G, Loher P, Rigoutsos I, Briasoulis E.The microRNAs within the DLK1-DIO3 genomic region: involvement in disease pathogenesis.Cell Mol Life Sci. 2012 Jul 24. 

  25. Delage B, Luong P, Maharaj L, O'Riain C, Syed N, Crook T, Hatzimichael E, Papoudou-Bai A, Mitchell TJ, Whittaker SJ, Cerio R, Gribben J, Lemoine N, Bomalaski J, Li CF, Joel S, Fitzgibbon J, Chen LT, Szlosarek PW. Promoter methylation of argininosuccinate synthetase-1 sensitises lymphomas to arginine deiminase treatment, autophagy and caspase-dependent apoptosis. Cell Death Dis 2012 Jul 5;3:e342

  26. Dranitsaris G, Hatzimichael E. Interpreting results from oncology clinical trials: a comparison of denosumab to zoledronic acid for the prevention of skeletal-related events in cancer patients. Support Care Cancer 2012 

  27. Hatzimichael E, Dasoula A, Kounnis V, Benetatos L, Lo Nigro C, Lattanzio L, et al. Bcl2-interacting killer CpG methylation in multiple myeloma: a potential predictor of relapsed/refractory disease with therapeutic implications. Leukemia & Lymphoma 2012
  28. Benetatos L, Vartholomatos G. Deregulated microRNAs in multiple myeloma. Cancer. 2012; 118(4): 878-87

  29. Hatzimichael E, Briasoulis E. Attitudes of people, authorities and doctors towards clinical cancer research: high expectations, neglected responsibilities and minimal involvement outline a hazy picture. Can we do any better?   Mediterranean Oncology Journal 2011: 1: 9-13

  30. Παθογένεια των μυελοδυσπλαστικών συνδρόμων ΙΙΙ: Ο ρόλος της επιγενετικής τροποποίησης. Ε. Χατζημιχαήλ, Λ. Μπενετάτος, Ε. Μπριασούλης, Haema 2011; 2: 169-176

  31. Pliakou XI, Koutsouka FP, Damigos D, Bourantas KL, Briasoulis EC, Voulgari PV. Rheumatoid arthritis in patients with hemoglobinopathies. Rheumatology Ιnternational 2011

  32. Benetatos L, Vartholomatos G, Hatzimichael E. MEG3 imprinted gene contribution in tumorigenesis. International Journal of Cancer 2011; 129(4): 773-9

  33. Benetatos L, Dasoula A, Hatzimichael E, Syed N, Voukelatou M, Dranitsaris G, et al. Polo-like kinase 2 (SNK/PLK2) is a novel epigenetically regulated gene in acute myeloid leukemia and myelodysplastic syndromes: genetic and epigenetic interactions. Annals of Hematology 2011; 90(9): 1037-45

  34. Ximeri M, Galanopoulos A, Klaus M, Parcharidou A, Giannikou K, Psyllaki M, et al. Effect of lenalidomide therapy on hematopoiesis of patients with myelodysplastic syndrome associated with chromosome 5q deletion. Haematologica 2010; 95:406-14

  35. Vartholomatos G, Benetatos L. Flow cytometric immunophenotyping for the diagnosis of a rare T-LGL neoplasm. Journal of Postgraduate Medicine 2010; 56:255 

  36. Lee S, Syed N, Taylor J, Smith P, Griffin B, Baens M, et al. DUSP16 is an epigenetically regulated determinant of JNK signalling in Burkitt's lymphoma. British Journal of Cancer 2010; 103:265-74

  37. Hatzimichael E, Dasoula A, Shah R, Syed N, Papoudou-Bai A, Coley HM, et al. The prolyl-hydroxylase EGLN3 and not EGLN1 is inactivated by methylation in plasma cell neoplasia. European Journal of Haematology 2010; 84:47-51

  38. Hatzimichael E, Dasoula A, Benetatos L, Syed N, Dranitsaris G, Crook T, et al. Study of specific genetic and epigenetic variables in multiple myeloma. Leukemia & Lymphoma 2010; 51:2270-4

  39. Giatromanolaki A, Bai M, Margaritis D, Bourantas KL, Koukourakis MI, Sivridis E, et al. Hypoxia and activated VEGF/receptor pathway in multiple myeloma. Anticancer Research 2010; 30:2831-6 

  40. Bourantas LK, Pappas G, Kapsali E, Gougopoulou D, Papamichail D, Bourantas KL. Brucellosis-induced autoimmune hemolytic anemia treated with rituximab. Annals of Pharmacotherapy 2010; 44(10): 1677-80 

  41. Benetatos L, Hatzimichael E, Dasoula A, Dranitsaris G, Tsiara S, Syrrou M, et al. CpG methylation analysis of the MEG3 and SNRPN imprinted genes in acute myeloid leukemia and myelodysplastic syndromes. Leukemia Research 2010; 34:148-53 

Featured publications from previous years
  1. Hatzimichael E, Dranitsaris G, Dasoula A, Benetatos L, Stebbing J, Crook T, et al. Von Hippel-Lindau methylation status in patients with multiple myeloma: a potential predictive factor for the development of bone disease. Clinical Lymphoma & Myeloma. 2009; 9:239-42 

  2. Hatzimichael E, Benetatos L, Dasoula A, Dranitsaris G, Tsiara S, Georgiou I, et al. Absence of methylation-dependent transcriptional silencing in TP73 irrespective of the methylation status of the CDKN2A CpG island in plasma cell neoplasia. Leukemia Research 2009;33:1272-5

  3. Benetatos L, Dova L, Baxevanos G, Kolaitis NI, Bourantas KL, Vartholomatos G. Peripheral blood flow cytometry based diagnosis in primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma: implications for more extensive use. Cytometry Part B, Clinical Cytometry 2009;76:102-6

  4. Vassou A, Bai M, Benetatos L, Tsili A, Bourantas K. Large B-cell transformation of chronic lymphocytic leukemia presenting as a penile mass and skin lesion. Hematology/Oncology and Stem Cell Therapy 2008;1:199-200

  5. Hatzimichael E, Dasoula A, Benetatos L, Makis A, Stebbing J, Crook T, et al. The absence of CDKN1C (p57KIP2) promoter methylation in myeloid malignancies also characterizes plasma cell neoplasms. British Journal of Haematology 2008;141:557-8 

  6. Benetatos L, Dasoula A, Syed N, Hatzimichael E, Crook T, Bourantas KL. Methylation analysis of the von Hippel-Lindau gene in acute myeloid leukaemia and myelodysplastic syndromes. Leukemia 2008;22:1293-5 

  7. Benetatos L, Dasoula A, Hatzimichael E, Georgiou I, Syrrou M, Bourantas KL. Promoter hypermethylation of the MEG3 (DLK1/MEG3) imprinted gene in multiple myeloma. Clinical Lymphoma & Myeloma 2008;8(3):171-5

  8. Benetatos L, Alymara V, Vassou A, Bourantas KL. Malignancies in beta-thalassemia patients: a single-center experience and a concise review of the literature. International Journal of Laboratory Hematology 2008;30:167-72

  9. Tsiara SN, Chaidos A, Bourantas LK, Kapsali HD, Bourantas KL. Recombinant human erythropoietin for the treatment of anaemia in patients with chronic idiopathic myelofibrosis. Acta Haematologica 2007;117:156-61

  10. Tsabouri S, Alimara V, Tsiara S, Vassiou A, Bourantas KL. Multiple complete remissions over a period of 6 years in a patient with acute myeloid leukemia after intensive chemotherapy. Leukemia & Lymphoma 2007;48:187-9

  11. Panteli K, Bai M, Hatzimichael E, Zagorianakou N, Agnantis NJ, Bourantas K. Serum levels, and bone marrow immunohistochemical expression of, vascular endothelial growth factor in patients with chronic myeloproliferative diseases. Hematology 2007;12:481-6

  12. Dimopoulos MA, Anagnostopoulos A, Kyrtsonis MC, Zervas K, Tsatalas C, Kokkinis G, et al. Primary treatment of Waldenstrom macroglobulinemia with dexamethasone, rituximab, and cyclophosphamide. Journal of Clinical Oncology 2007;25:3344-9

  13. Benetatos L, Hatzimichael E, Vassou A, Bourantas KL. Cryptococcus lung infection complicating fludarabine treatment in a chronic lymphocytic leukemia patient. Leukemia Research 2007;31:119-20

  14. Vassou A, Alymara V, Agelis E, Stefanaki S, Bourantas KL. Multifocal extramedullary plasmacytoma with paraproteinemia, pleural involvement and retroperitoneal lymphadenopathy: an uncommon pattern of relapse of solitary osseous plasmacytoma. Annals of Hematology 2006;85:335-6   

  15. Makis AC, Hatzimichael EC, Stebbing J, Bourantas KL. C-reactive protein and vascular cell adhesion molecule-1 as markers of severity in sickle cell disease. Archives of Internal Medicine 2006;166:366-8

  16. Hatzimichael E, Benetatos L, Stebbing J, Kapsali E, Panayiotopoulou S, Bourantas KL. Spontaneous splenic haematoma in a multiple myeloma patient receiving pegfilgrastim support. Clinical and Laboratory Haematology 2006;28:416-8 

  17. Dimopoulos MA, Anagnostopoulos A, Terpos E, Repoussis P, Zomas A, Katodritou E, Kyrtsonis MC, Delibasi S, Vassou A, et al. Primary treatment with pulsed melphalan, dexamethasone and thalidomide for elderly symptomatic patients with multiple myeloma. Haematologica 2006;91:252-4 
 

 

 

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