Carcinogenesis Advance Access originally published online on July 16, 2008
Carcinogenesis 2008 29(10):2025-2034; doi:10.1093/carcin/bgn168
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MN1 affects expression of genes involved in hematopoiesis and can enhance as well as inhibit RAR/RXR-induced gene expression
1 Department of Pathology, Josephine Nefkens Institute, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands
2 Department of Genetics and Tumor Cell Biology, St Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA
3 Department of Clinical Genetics, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands
4 Erasmus Center of Biomics, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands
* To whom correspondence should be addressed. Tel: +31 10 7043929; Fax: +31 10 7044762; Email: e.zwarthoff{at}erasmusmc.nl
The oncoprotein meningioma 1 (MN1) is overexpressed in several subtypes of acute myeloid leukemia (AML) and overexpression was associated with a poor response to chemotherapy. MN1 is a cofactor of retinoic acid receptor/retinoic x receptor (RAR/RXR)-mediated transcription and this study identified genes in the promonocytic cell line U937 that were regulated by MN1. We found that MN1 can both stimulate and inhibit transcription. Combining MN1 expression with all-trans retinoic acid (ATRA), the ligand of the RAR/RXR dimer, showed that MN1 could both enhance and repress ATRA effects. Many of the identified genes are key players in hematopoiesis and leukemogenesis (e.g. MEIS1 and BMI1). Another interesting target is DHRS9. DHRS9 is involved in the synthesis of ATRA from vitamin A. MN1 inhibited DHRS9 expression and completely abolished its induction by ATRA. MN1 is also the target of a rare AML-causing translocation encoding the MN1–TEL protein. MN1–TEL induces expression of only a few genes and its most pronounced effect is inhibition of a large group of ATRA-induced genes including DHRS9. In conclusion, both MN1 and MN1–TEL interfere with the ATRA pathway and this might explain the differentiation block in leukemias in which these genes are involved.
Abbreviations: AML, acute myeloid leukemia; ATRA, all-trans retinoic acid; BM, bone marrow; cDNA, complementary DNA; ETS, E26 transformation-specific; RAR/RXR, retinoic acid receptor/retinoic x receptor; qPCR, quantitative polymerase chain reaction
These authors contributed equally to this work. Received January 25, 2008; revised July 8, 2008; accepted July 11, 2008.
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