Inhibition of retinoic acid receptor signaling by Ski in acute myeloid leukemia

• Published in: Leukemia Vol. 20; no. 3; pp. 437 - 443
• Main Authors: RITTER, M, KATTMANN, D, JÄGER, R, EHNINGER, G, SCHÄFER, H, UEKI, N, HAYMAN, M. J, EILERS, M, NEUBAUER, A, TEICHLER, S, HARTMANN, O, SAMUELSSON, M. K. R, BURCHERT, A, BACH, J.-P, KIM, T. D, BERWANGER, B, THIEDE, C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01-03-2006; Nature Publishing Group
• Subjects: Acids; Acute Disease; Acute myeloid leukemia; Adolescent; Adult; Aged; Aged, 80 and over; Biological and medical sciences; Bone marrow; Bone marrow transplantation; CD34 antigen; Chromosome Deletion; Chromosomes, Human, Pair 7; Cytogenetics; DNA microarrays; DNA-Binding Proteins - metabolism; Enzyme Inhibitors - pharmacology; Female; Fluorescent Antibody Technique; Gene expression; Hematologic and hematopoietic diseases; Histone deacetylase; Histone Deacetylase Inhibitors; Humans; Karyotypes; Kinases; Leukemia; Leukemia, Myeloid - genetics; Leukemia, Myeloid - metabolism; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Male; Medical sciences; Middle Aged; Patients; Proto-Oncogene Proteins - metabolism; Receptors; Receptors, Retinoic Acid - antagonists & inhibitors; Receptors, Retinoic Acid - metabolism; Retinoic acid; Retinoic acid receptors; Signal Transduction; Signaling; Ski protein; Stem cells; Transcription; Valproic acid; Valproic Acid - pharmacology; Germany; Chromosomal aberration; Human; retinoic acid signaling; Acute; Retinoid; Ski oncogene; Aneuploidy; Malignant hemopathy; Chromosome C7; Signal transduction; monosomy 7; acute myeloid leukemia; Onc gene; Retinoic acid; Monosomy; Protooncogene; Acute myelocytic leukemia; RAR retinoic acid receptor
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2404093

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.