title: Histone modifications patterns in tissues and tumours from acute promyelocytic leukemia xenograft model in response to combined epigenetic therapy.
abstract: Xenograft models are suitable for in vivo study of leukemia's pathogenesis and the preclinical development of anti-leukemia agents but understanding of epigenetic regulatory mechanisms linking to adult cell functions in pathological conditions during different in vivo treatments is yet unknown. In this study, for the first time epigenetic chromatin modifications were characterized in tissues and tumours from murine xenograft model generated using the human acute promyelocytic leukemia (APL) NB4 cells engrafted in immunodeficient NOG mice. Xenografts were subjected to combined epigenetic treatment by histone deacetylase inhibitor Belinostat, histone methyltransferase inhibitor 3-DZNeaplanocin A and all-trans-retinoic acid based on in vitro model, where such combination inhibited NB4 cell growth and enhanced retinoic acid-induced differentiation to granulocytes. Xenotransplantation was assessed by peripheral blood cells counts, the analysis of cell surface markers (CD15, CD33, CD45) and the expression of certain genes (PML-RAR alpha, CSF3, G-CSFR, WT1). The combined treatment prolonged APL xenograft mice survival and prevented tumour formation. The analysis of the expression of histone marks such as acetylation of H4, trimethylation of H3K4, H3K9 and H3K27 in APL xenograft mice tumours and tissues demonstrated tissue-specific changes in the level of histone modifications and the APL prognostic mark, WT1 protein. In summary, the effects of epigenetic agents used in this study were positive for leukemia prevention and linked to a modulation of the chromatin epigenetic environment in adult tissues of malignant organism.
authors.affiliation: Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, LT-08662 Vilnius, Lithuania.
authors.forename: Giedrė
authors.initials: G
authors.lastname: Valiulienė
authors.affiliation: Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, LT-08662 Vilnius, Lithuania.
authors.forename: Gražina
authors.initials: G
authors.lastname: Treigytė
authors.affiliation: Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, LT-08662 Vilnius, Lithuania.
authors.forename: Jūratė
authors.initials: J
authors.lastname: Savickienė
authors.affiliation: Electronic Systems Department, Electronics Faculty, Vilnius Gediminas Technical University, Naugarduko 41-422, LT-03227 Vilnius, Lithuania.
authors.forename: Dalius
authors.initials: D
authors.lastname: Matuzevičius
authors.affiliation: Department of Biological Models, Institute of Biochemistry, Vilnius University, LT-08662 Vilnius, Lithuania.
authors.forename: Milda
authors.initials: M
authors.lastname: Alksnė
authors.affiliation: Department of Biological Models, Institute of Biochemistry, Vilnius University, LT-08662 Vilnius, Lithuania.
authors.forename: Rasa
authors.initials: R
authors.lastname: Jarašienė-Burinskaja
authors.affiliation: Department of Biological Models, Institute of Biochemistry, Vilnius University, LT-08662 Vilnius, Lithuania.
authors.forename: Virginija
authors.initials: V
authors.lastname: Bukelskienė
authors.affiliation: Electronic Systems Department, Electronics Faculty, Vilnius Gediminas Technical University, Naugarduko 41-422, LT-03227 Vilnius, Lithuania.
authors.forename: Dalius
authors.initials: D
authors.lastname: Navakauskas
authors.affiliation: Department of Molecular Cell Biology, Institute of Biochemistry, Vilnius University, LT-08662 Vilnius, Lithuania. Electronic address: ruta.navakauskiene@bchi.vu.lt.
authors.forename: Rūta
authors.initials: R
authors.lastname: Navakauskienė
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic / Q000187:drug effects; D005260:Female; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D009928:Organ Specificity / Q000187:drug effects; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use; D025721:WT1 Proteins / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D006657:Histones; D006877:Hydroxamic Acids; D013449:Sulfonamides; D025721:WT1 Proteins; D014212:Tretinoin; C487081:belinostat
keywords: 3-DZNeaplanocin A; Acute promyelocytic leukemia; Belinostat; Histone modifications; WT1