title: Novel role of HDAC inhibitors in AML1/ETO AML cells: activation of apoptosis and phagocytosis through induction of annexin A1.
abstract: The chimeric fusion protein AML1-ETO, created by the t(8;21) translocation, recruits histone deacetylase (HDAC) to AML1-dependent promoters, resulting in transcriptional repression of the target genes. We analyzed the transcriptional changes in t(8;21) Kasumi-1 AML cells in response to the HDAC inhibitors, depsipeptide (FK228) and suberoylanilide hydroxamic acid (SAHA), which induced marked growth inhibition and apoptosis. Using cDNA array, annexin A1 (ANXA1) was identified as one of the FK228-induced genes. Induction of ANXA1 mRNA was associated with histone acetylation in ANXA1 promoter and reversal of the HDAC-dependent suppression of C/EBPalpha by AML1-ETO with direct recruitment of C/EBPalpha to ANXA1 promoter. This led to increase in the N-terminal cleaved isoform of ANXA1 protein and accumulation of ANXA1 on cell membrane. Neutralization with anti-ANXA1 antibody or gene silencing with ANXA1 siRNA inhibited FK228-induced apoptosis, suggesting that the upregulation of endogenous ANXA1 promotes cell death. FK228-induced ANXA1 expression was associated with massive increase in cell attachment and engulfment of Kasumi-1 cells by human THP-1-derived macrophages, which was completely abrogated with ANXA1 knockdown via siRNA transfection or ANXA1 neutralization. These findings identify a novel mechanism of action of HDAC inhibitors, which induce the expression and externalization of ANXA1 in leukemic cells, which in turn mediates the phagocytic clearance of apoptotic cells by macrophages.
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Blood and Marrow Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Tabe
authors.forename: L
authors.initials: L
authors.lastname: Jin
authors.forename: R
authors.initials: R
authors.lastname: Contractor
authors.forename: D
authors.initials: D
authors.lastname: Gold
authors.forename: P
authors.initials: P
authors.lastname: Ruvolo
authors.forename: S
authors.initials: S
authors.lastname: Radke
authors.forename: Y
authors.initials: Y
authors.lastname: Xu
authors.forename: Y
authors.initials: Y
authors.lastname: Tsutusmi-Ishii
authors.forename: K
authors.initials: K
authors.lastname: Miyake
authors.forename: N
authors.initials: N
authors.lastname: Miyake
authors.forename: S
authors.initials: S
authors.lastname: Kondo
authors.forename: A
authors.initials: A
authors.lastname: Ohsaka
authors.forename: I
authors.initials: I
authors.lastname: Nagaoka
authors.forename: M
authors.initials: M
authors.lastname: Andreeff
authors.forename: M
authors.initials: M
authors.lastname: Konopleva
mesh_terms: D000107:Acetylation; D017305:Annexin A1 / Q000096:biosynthesis* / Q000235:genetics; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050676:Core Binding Factor Alpha 2 Subunit / Q000378:metabolism*; D018076:DNA, Complementary / Q000235:genetics; D047630:Depsipeptides / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D056572:Histone Deacetylase Inhibitors; D006657:Histones / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008264:Macrophages / Q000502:physiology; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D010587:Phagocytosis / Q000187:drug effects; D000075142:RUNX1 Translocation Partner 1 Protein; D015854:Up-Regulation / Q000187:drug effects; D000077337:Vorinostat
chemical_list: C107844:AML1-ETO fusion protein, human; D017305:Annexin A1; D000970:Antineoplastic Agents; D050676:Core Binding Factor Alpha 2 Subunit; D018076:DNA, Complementary; D047630:Depsipeptides; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006657:Histones; D006877:Hydroxamic Acids; D015514:Oncogene Proteins, Fusion; D000075142:RUNX1 Translocation Partner 1 Protein; D000077337:Vorinostat; C087123:romidepsin