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

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 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 signalling 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-2 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 differentiation of APL cells will, ultimately, allow recognizing new possible targets for future therapies of APL patients