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Blood, 15 May 2007, Vol. 109, No. 10, pp. 4399-4405.
Prepublished online as a Blood First Edition Paper on February 6, 2007; DOI 10.1182/blood-2006-09-045104.


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Submitted September 1, 2006
Accepted January 24, 2007

Expression of the miR-17-92 polycistron in chronic myeloid leukemia (CML) CD34+ cells

Letizia Venturini, Karin Battmer, Mirco Castoldi, Beate Schultheis, Andreas Hochhaus, Martina U Muckenthaler, Arnold Ganser, Matthias Eder*, and Michaela Scherr

Hannover Medical School, Department of Hematology, Hemostasis and Oncology, Hannover, Germany
Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg, Germany
III. Medical Clinic, University Hospital of Mannheim, University of Heidelberg, Mannheim, Germany

* Corresponding author; email: eder.matthias{at}mh-hannover.de.

Aberrant micro RNA (miRNA) expression has been described in human malignancies including B-cell lymphomas. We here report BCR-ABL and c-MYC dependent regulation of miRNA expression in CML using microarray analysis (miCHIP) and miRNA-specific quantitative real-time RT-PCR. In three bcr-abl positive cell lines, expression of miRNAs encoded within the polycistronic miR-17-92 cluster is specifically down-regulated (2- 5-fold) by both imatinib treatment and anti-bcr-abl RNAi. In addition, anti-c-myc-RNAi reduces miR-17-92 expression in K562 cells in which miRNAs can specifically repress reporter gene expression as demonstrated by specific miRNA inhibition with antagomirs. Furthermore, lentivirus-mediated over-expression of polycistronic miRNAs in K562 cells confers increased proliferation, partial resistance against anti-c-myc-RNAi, and enhanced sensitivity to imatinib induced cell death. Finally, we determined miR-17-92 expression in purified normal (n=4), early chronic phase (n=24) and blast crisis (n=7) CML CD34+ cells and found up-regulation of polycistronic pri-miRNA transcripts and mature miRNAs in chronic phase but not in blast crisis CML. This data are in accordance with a BCR-ABL - c-MYC - miR-17-92 pathway which mediates enhanced miRNA expression in chronic phase but not blast crisis CML CD34+ cells. Altered miRNA expression may contribute to the pathophysiology of the disease and may provide potential targets for therapeutic intervention.


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