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 Blood, 8 January 2009, Vol. 113, No. 2, pp. 412-421.
Prepublished online as a Blood First Edition Paper on October 21, 2008; DOI 10.1182/blood-2008-05-158139.

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MYELOID NEOPLASIA

Transcriptional repression of microRNA genes by PML-RARA increases expression of key cancer proteins in acute promyelocytic leukemia

Anne Saumet1, Guillaume Vetter2, Manuella Bouttier3, Elodie Portales-Casamar4, Wyeth W. Wasserman4, Thomas Maurin5, Bernard Mari5, Pascal Barbry5, Laurent Vallar6, Evelyne Friederich2, Khalil Arar7, Bruno Cassinat8, Christine Chomienne8, and Charles-Henri Lecellier3

1 Institut de Génétique Humaine, CNRS UPR1142, Montpellier, France; 2 Université du Luxembourg, Luxembourg, Luxembourg; 3 Institut de Génétique Moléculaire de Montpellier, CNRS UMR5535-IFR122, Université de Montpellier, Montpellier, France; 4 University of British Columbia, Vancouver, BC, Canada; 5 Institut de Pharmacologie Moléculaire et Cellulaire, UMR6097 CNRS/UNSA, Sophia Antipolis, France; 6 CRP-Santé, Luxembourg, Luxembourg; 7 Sigma-Proligo, Evry, France; and 8 Institut Universitaire d'Hématologie, Inserm U718, Hôpital St Louis, Paris, France

Micro(mi)RNAs are small noncoding RNAs that orchestrate many key aspects of cell physiology and their deregulation is often linked to distinct diseases including cancer. Here, we studied the contribution of miRNAs in a well-characterized human myeloid leukemia, acute promyelocytic leukemia (APL), targeted by retinoic acid and trioxide arsenic therapy. We identified several miRNAs transcriptionally repressed by the APL-associated PML-RAR oncogene which are released after treatment with all-trans retinoic acid. These coregulated miRNAs were found to control, in a coordinated manner, crucial pathways linked to leukemogenesis, such as HOX proteins and cell adhesion molecules whose expressions are thereby repressed by the chemotherapy. Thus, APL appears linked to transcriptional perturbation of miRNA genes, and clinical protocols able to successfully eradicate cancer cells may do so by restoring miRNA expression. The identification of abnormal miRNA biogenesis in cancer may therefore provide novel biomarkers and therapeutic targets in myeloid leukemias.


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