title: Clonogenic acute myelogenous leukemia cells are heterogeneous with regard to regulation of differentiation and effect of epigenetic pharmacological targeting.
abstract: Differentiation-inducing therapy with the DNA-methylation inhibitor Decitabine (5'-aza-deoxycytidine) and histone deacetylase (HDAC) inhibitors are now considered in acute myelogenous leukemia (AML). We investigated the in vitro effects of Decitabine and two structurally unrelated HDAC inhibitors (Sodium 4-phenyl butyrate, Tricostatin A) on clonogenic AML cells. Based on morphological criteria we identified four major colony types: (i) non-erythroid colonies, (ii) erythroid colonies that were detected only for a subset of patients and could be further sub classified into mature and immature forms, and (iii) intermediate colonies. Erythroid differentiation was associated with low CD34 expression. The colonies showed differences in morphology, viability, cell cycle distribution and expression of differentiation markers. Both Decitabine and the two HDAC inhibitors altered AML cell expression of differentiation markers, whereas the drugs did not have any major influence on cell cycle distribution. However, the pharmacological effects differed between the four colony subsets, and differences were also detected between the two HDAC inhibitors. We conclude that clonogenic AML cells can be classified into well-defined subsets based on their differentiation, and these subsets differ in their biological characteristics as well as their response to pharmacological targeting of epigenetic regulation.
authors.affiliation: Division for Hematology, Department of Medicine, Haukeland University Hospital and University of Bergen, N-5021 Bergen, Norway. anita.ryningen@mbi.uib.no
authors.forename: Anita
authors.initials: A
authors.lastname: Ryningen
authors.forename: Camilla
authors.initials: C
authors.lastname: Stapnes
authors.forename: Øystein
authors.initials: Ø
authors.lastname: Bruserud
mesh_terms: D000208:Acute Disease; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000031:analogs & derivatives / Q000494:pharmacology; D002453:Cell Cycle / Q000187:drug effects; D002454:Cell Differentiation; D049109:Cell Proliferation; D004272:DNA, Mitochondrial / Q000378:metabolism; D000077209:Decitabine; D004791:Enzyme Inhibitors / Q000494:pharmacology; D044127:Epigenesis, Genetic / Q000187:drug effects*; D005260:Female; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007951:Leukemia, Myeloid / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy; D010654:Phenylbutyrates / Q000494:pharmacology; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014410:Tumor Stem Cell Assay
chemical_list: D000970:Antineoplastic Agents; D004272:DNA, Mitochondrial; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D010654:Phenylbutyrates; C012589:trichostatin A; D000077209:Decitabine; C075773:4-phenylbutyric acid; D001374:Azacitidine; D013936:Thymidine