title: Antagonism between granulocytic maturation and deacetylase inhibitor-induced apoptosis in acute promyelocytic leukaemia cells.
abstract: BACKGROUND
  Transcriptional repression is a key mechanism driving leukaemogenesis. In acute promyelocytic leukaemia (APL), the fusion protein promyelocytic leukaemia-retinoic acid receptor-α fusion (PML-RARα) recruits transcriptional repressors to myeloid differentiation genes. All-trans-retinoic acid (ATRA) induces the proteasomal degradation of PML-RARα and granulocytic differentiation. Histone deacetylases (HDACs) fall into four classes (I-IV) and contribute to the transcription block caused by PML-RARα.
  
  
  METHODS
  Immunoblot, flow cytometry, and May-Grünwald-Giemsa staining were used to analyze differentiation and induction of apoptosis.
  
  
  RESULTS
  A PML-RARα- and ATRA-dependent differentiation programme induces granulocytic maturation associated with an accumulation of the myeloid transcription factor CCAAT/enhancer binding protein (C/EBP)ɛ and of the surface protein CD11b. While this process protects APL cells from inhibitors of class I HDAC activity, inhibition of all Zinc-dependent HDACs (classes I, II, and IV) with the pan-HDACi (histone deacetylase inhibitor(s)) LBH589 induces apoptosis of immature and differentiated APL cells. LBH589 can eliminate C/EBPɛ and the mitochondrial apoptosis regulator B-cell lymphoma (BCL)-xL in immature and differentiated NB4 cells. Thus, BCL-xL and C/EBPɛ are newly identified molecular markers for the efficacy of HDACi against APL cells.
  
  
  CONCLUSIONS
  Our results could explain the therapeutic limitations occurring with ATRA and class I HDACi combinations. Pro-apoptotic effects caused by pan-HDAC inhibition are not blunted by ATRA-induced differentiation and may provide a clinically interesting alternative.
authors.affiliation: Center for Molecular Biomedicine (CMB), Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, Hans-Knöll-Strasse 2, 07745 Jena, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Hennig
authors.affiliation: University Hospital Jena, Institute for Immunology, Friedrich-Schiller-University Jena, Leutragraben 3, 07743 Jena, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Müller
authors.affiliation: Department of Transfusion Medicine, Cell Therapy and Haemostasis, Ludwig-Maximilian University Hospital, Max-Lebsche Platz 32, 81377 Munich, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Wichmann
authors.affiliation: University Hospital Jena, Institute for Immunology, Friedrich-Schiller-University Jena, Leutragraben 3, 07743 Jena, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Drube
authors.affiliation: Center for Molecular Biomedicine (CMB), Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, Hans-Knöll-Strasse 2, 07745 Jena, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Pietschmann
authors.affiliation: Institute of Physiology I, Eberhard-Karls-University Tübingen, Gmelinstrasse 5, 72076 Tübingen, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Pelzl
authors.affiliation: Institute for Biomedical Research, Georg-Speyer-Haus, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt/Main, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Grez
authors.affiliation: Department of Medicine, Hematology/Oncology, Johann Wolfgang Goethe-University Frankfurt/Main, Theodor-Stern-Kai 7, 60596 Frankfurt/Main, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Bug
authors.affiliation: Center for Molecular Biomedicine (CMB), Institute of Biochemistry and Biophysics, Friedrich-Schiller-University Jena, Hans-Knöll-Strasse 2, 07745 Jena, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Heinzel
authors.affiliation: Department of Toxicology, University Medical Center, Obere Zahlbacher Strasse 67, 55131 Mainz, Germany.
authors.forename: O H
authors.initials: OH
authors.lastname: Krämer
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic; D006098:Granulocytes / Q000502:physiology*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D015473:Leukemia, Promyelocytic, Acute; D000077767:Panobinostat; D014212:Tretinoin / Q000494:pharmacology*; D051020:bcl-X Protein / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C494811:BCL2L1 protein, human; D022762:CCAAT-Enhancer-Binding Proteins; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D051020:bcl-X Protein; C070790:CEBPE protein, human; D014212:Tretinoin; D000077767:Panobinostat