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Carcinogenesis Advance Access published online on July 16, 2008
Carcinogenesis, doi:10.1093/carcin/bgn168
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

MN1 affects expression of genes involved in hematopoiesis and can enhance as well as inhibit RAR/RXR induced gene expression

Magda A. Meester-Smoor1,5, Marjolein J. F. W. Janssen1,5, Gerard C. Grosveld2, Annelies de Klein3, Wilfred F. J. van IJcken4, Hannie Douben3 and Ellen C. Zwarthoff1

1 Department of Pathology, Josephine Nefkens Institute, Erasmus MC, P.O. 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, Rotterdam, The Netherlands
4 Erasmus Center of Biomics, Erasmus MC, Rotterdam, The Netherlands

Correspondence: Dr. E.C. Zwarthoff, Department of Pathology, Josephine Nefkens Institute, Erasmus MC, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands. Tel.: +31-10-7043929, Fax: +31-10-7044762, E-mail: e.zwarthoff{at}erasmusmc.nl

The oncoprotein MN1 is overexpressed in several subtypes of acute myeloid leukemia (AML) and overexpression was associated with a poor reponse to chemotherapy. MN1 is a co-factor 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 MN1TEL interfere with the ATRA pathway and this might explain the differentiation block in leukemias in which these genes are involved.

Key Words: retinoic acid • acute myeloid leukemia • DHRS9 • leukemogenesis • MN1

5 Authors contributed equally to this work

Received January 25, 2008; revised July 8, 2008; accepted July 11, 2008.


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