title: Therapeutic targeting of transcription in acute promyelocytic leukemia by use of an inhibitor of histone deacetylase.
abstract: BACKGROUND
  Acetylation of DNA-associated histones is linked to activation of gene transcription, whereas histone deacetylation is associated with transcriptional repression. Recent studies have shown that inhibitors of histone deacetylases can relieve transcriptional repression caused by the products of certain oncogenes. We tested whether these findings could be applied clinically to a patient with highly resistant acute promyelocytic leukemia.
  
  
  METHODS
  A patient who had experienced multiple relapses was treated with all-trans-retinoic acid alone and in combination with sodium phenylbutyrate, an inhibitor of histone deacetylases. Immunohistochemistry and western blot analysis were used to assay for histone hyperacetylation in mononuclear cells from the patient's blood and bone marrow. Marrow mononuclear cells and reverse transcription-polymerase chain reaction (RT-PCR) analysis of messenger RNA encoded by the PML/RAR-alpha oncogene were used to assess minimal residual disease.
  
  
  RESULTS
  The patient proved clinically resistant to treatment with all-trans-retinoic acid alone. However, 23 days after sodium phenylbutyrate was added to the treatment regimen, visible leukemic cells had been eliminated from her bone marrow, and she achieved a complete clinical and cytogenetic remission shortly thereafter. With a second treatment course, analysis for minimal residual disease by RT-PCR proved negative. Immunofluorescence and western blot analysis showed that phenylbutyrate caused a time-dependent increase in histone acetylation in blood and bone marrow mononuclear cells.
  
  
  CONCLUSIONS
  Clinical treatment with an inhibitor of histone deacetylase induces histone hyperacetylation in target cells and may restore sensitivity to the anti-leukemic effects of all-trans-retinoic acid in acute promyelocytic leukemia. Similar therapy may prove useful in other neoplastic diseases that are associated with oncogenic repression of gene transcription due to recruitment of histone deacetylases.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, and the Cornell University Medical College, New York, NY 10021, USA. rwarrell@mskcc.org
authors.forename: R P
authors.initials: RP
authors.lastname: Warrell
authors.forename: L Z
authors.initials: LZ
authors.lastname: He
authors.forename: V
authors.initials: V
authors.lastname: Richon
authors.forename: E
authors.initials: E
authors.lastname: Calleja
authors.forename: P P
authors.initials: PP
authors.lastname: Pandolfi
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D015153:Blotting, Western; D004334:Drug Administration Schedule; D005260:Female; D005455:Fluorescent Antibody Technique; D006655:Histone Deacetylases / Q000187:drug effects*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000201:enzymology; D010654:Phenylbutyrates / Q000008:administration & dosage; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014158:Transcription, Genetic / Q000187:drug effects*; D014212:Tretinoin / Q000008:administration & dosage
chemical_list: D010654:Phenylbutyrates; D014212:Tretinoin; C075773:4-phenylbutyric acid; D006655:Histone Deacetylases