title: Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia.
abstract: Acute myeloid leukemia (AML) is a heterogeneous disease with multiple different cytogenetic and molecular aberrations contributing to leukemic transformation. We compared gene expression profiles of 4608 genes using cDNA-arrays from 20 AML patients (nine with -7/del7q and 11 with normal karyotype) with 23 CD34+ preparations from healthy bone marrow donors. SKI, a nuclear oncogene, was highly up regulated. In a second set of 183 AML patients analyzed with real-time PCR, the highest expression level of SKI in AML with -7/del7q could be confirmed. As previously described, Ski associates with the retinoic acid receptor (RAR) complex and can repress transcription. We wanted to investigate the interference of Ski with RARalpha signaling in AML. Ski was co-immunoprecipitated and colocalized with RARalpha. We also found that overexpression of wild-type Ski inhibited the prodifferentiating effects of retinoic acid in U937 leukemia cells. Mutant Ski, lacking the N-CoR binding, was no more capable of repressing RARalpha signaling. The inhibition by wild-type Ski could partially be reverted by the histone deacetylase blocking agent valproic acid. In conclusion, Ski seems to be involved in the blocking of differentiation in AML via inhibition of RARalpha signaling.
authors.affiliation: Klinik für Innere Medizin mit SP Hämatologie, Onkologie und Immunologie, Philipps-Universität, Marburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ritter
authors.forename: D
authors.initials: D
authors.lastname: Kattmann
authors.forename: S
authors.initials: S
authors.lastname: Teichler
authors.forename: O
authors.initials: O
authors.lastname: Hartmann
authors.forename: M K R
authors.initials: MK
authors.lastname: Samuelsson
authors.forename: A
authors.initials: A
authors.lastname: Burchert
authors.forename: J-P
authors.initials: JP
authors.lastname: Bach
authors.forename: T D
authors.initials: TD
authors.lastname: Kim
authors.forename: B
authors.initials: B
authors.lastname: Berwanger
authors.forename: C
authors.initials: C
authors.lastname: Thiede
authors.forename: R
authors.initials: R
authors.lastname: Jäger
authors.forename: G
authors.initials: G
authors.lastname: Ehninger
authors.forename: H
authors.initials: H
authors.lastname: Schäfer
authors.forename: N
authors.initials: N
authors.lastname: Ueki
authors.forename: M J
authors.initials: MJ
authors.lastname: Hayman
authors.forename: M
authors.initials: M
authors.lastname: Eilers
authors.forename: A
authors.initials: A
authors.lastname: Neubauer
mesh_terms: D000208:Acute Disease; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002872:Chromosome Deletion; D002897:Chromosomes, Human, Pair 7; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005455:Fluorescent Antibody Technique; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D007951:Leukemia, Myeloid / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D014635:Valproic Acid / Q000494:pharmacology
chemical_list: D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D011518:Proto-Oncogene Proteins; D018168:Receptors, Retinoic Acid; C060614:SKI protein, human; D014635:Valproic Acid