GENE SILENCING PART I 

Minerva Biotecnologica 2008 March;20(1):39-49

Copyright © 2008 EDIZIONI MINERVA MEDICA

language: English

RNA interference in the study of molecular mechanisms activated during agonist induced differentiation of acute promyelocytic leukemia derived promyelocytes

Brugnoli F. ¹, Grassilli S. ¹, Benedusi M. ¹, Capitani S. ^{1, 2}, Bertagnolo V. ¹

¹ Signal Transduction Unit, Laboratory of Cell Biology Section of Human Anatomy, Department of Morphology and Embryology, University of Ferrara, Ferrara, Italy 2 MIUR ICSI (Interdisciplinary Center for the Study of Inflammation) University of Ferrara, Ferrara, Italy

Acute promyelocytic leukemia (APL), the M3 subtype of acute myeloid leukemia, is one of the most successful examples of translational research in medicine, since the coordinated combination of laboratory and clinical studies has transformed this leukemia from a fatal into a curable disease. In particular, the introduction of all-trans retinoic acid (ATRA) in APL therapy opened a new page in the history of tumor treatment, since this agonist is capable of inducing morphologic and functional maturation of APL blasts. In both APL blasts and APL-derived cell lines, ATRA-induced progression of promyelocytes to a more mature state is mediated through a complex regulation of gene transcription. The events mediated by proteins codified by ATRA target genes that account for the complex and integrated network of intracellular signaling pathways responsible of the completion of maturation, are still largely unknown. In the last few years, the application of siRNA procedures to the study of molecular mechanisms that lead tumoral myeloid precursors to maturate along the granulocytic lineage has permitted to establish the specific role of a number of intracellular signaling molecules in a wide range of cell functions, including cell cycle regulation and control of gene expression. In particular, for some of these, as PLC-b2 and Vav1, it was established a role in promoting maturation of APL-derived promyelocytes and in regulating the modifications of the cytoskeleton architecture that accompany maturation related motility and migration. The identification of molecules that play crucial roles in the differentiation of APL cells will, ultimately, allow recognizing new possible targets for future therapies of APL patients.