title: Histone deacetylase-targeted treatment restores retinoic acid signaling and differentiation in acute myeloid leukemia.
abstract: Histone deacetylase (HDAC)-dependent transcriptional repression of the retinoic acid (RA)-signaling pathway underlies the differentiation block of acute promyelocytic leukemia. RA treatment relieves transcriptional repression and triggers differentiation of acute promyelocytic leukemia blasts, leading to disease remission. We report that transcriptional repression of RA signaling is a common mechanism in acute myeloid leukemias (AMLs). HDAC inhibitors restored RA-dependent transcriptional activation and triggered terminal differentiation of primary blasts from 23 AML patients. Accordingly, we show that AML1/ETO, the commonest AML-associated fusion protein, is an HDAC-dependent repressor of RA signaling. These findings relate alteration of the RA pathway to myeloid leukemogenesis and underscore the potential of transcriptional/differentiation therapy in AML.
authors.affiliation: Department of Histology and Medical Embryology, University of Rome La Sapienza, Italy.
authors.forename: F F
authors.initials: FF
authors.lastname: Ferrara
authors.forename: F
authors.initials: F
authors.lastname: Fazi
authors.forename: A
authors.initials: A
authors.lastname: Bianchini
authors.forename: F
authors.initials: F
authors.lastname: Padula
authors.forename: V
authors.initials: V
authors.lastname: Gelmetti
authors.forename: S
authors.initials: S
authors.lastname: Minucci
authors.forename: M
authors.initials: M
authors.lastname: Mancini
authors.forename: P G
authors.initials: PG
authors.lastname: Pelicci
authors.forename: F
authors.initials: F
authors.lastname: Lo Coco
authors.forename: C
authors.initials: C
authors.lastname: Nervi
mesh_terms: D000107:Acetylation; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology; D050676:Core Binding Factor Alpha 2 Subunit; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000502:physiology; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D015479:Leukemia, Myelomonocytic, Acute / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000096:biosynthesis / Q000235:genetics; D000075142:RUNX1 Translocation Partner 1 Protein; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014212:Tretinoin / Q000494:pharmacology* / Q000502:physiology; D014407:Tumor Cells, Cultured
chemical_list: C107844:AML1-ETO fusion protein, human; D000970:Antineoplastic Agents; D050676:Core Binding Factor Alpha 2 Subunit; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D014157:Transcription Factors; C012589:trichostatin A; D014212:Tretinoin; D006655:Histone Deacetylases