reduction of prep1 levels affects differentiation of normal and malignant b cells and accelerates myc driven lymphomagenesis减少prep1水平影响正常和恶性b细胞的分化和加速myc便驱动.pdfVIP

Reduction of Prep1 Levels Affects Differentiation of Normal and Malignant B Cells and Accelerates Myc Driven Lymphomagenesis 1 1 1 2 3 1 Giorgio Iotti , Stefania Mejetta , Livia Modica , Dmitry Penkov , Maurilio Ponzoni , Francesco Blasi * 1 Laboratory of Transcriptional Regulation in Development and Cancer, IFOM (Fondazione Istituto FIRC di Oncologia Molecolare), Milano, Italy, 2 Department of Basic Medicine, Moscow State University, Moscow, Russia, 3 Department of Pathology, San Raffaele Scientific Institute, Milan, Italy Abstract The Prep1 homeodomain transcription factor has recently been recognized as a tumor suppressor. Among other features, haploinsufficiency of Prep1 is able to strongly accelerate the B-lymphomagenesis in EmMyc mice. Now we report that this occurs concomitantly with a change in the type of B-cell lymphomas generated by the Myc oncogene. Indeed, the tumors generated in the EmMyc-Prep1+/ 2 mice are much more immature, being mostly made up of Pro-B or Pre-B cells, while those in the EmMyc-Prep1+/+ + mice are more differentiated being invariably IgM . Moreover, we show that Prep1 is in fact required for the differentiation of Pro-B and Pre-B cells into IgM+ lymphocytes and/or their proliferation, thus showing also how a normal function of Prep1 affects EmMyc lymphomagenesis. Finally, we show that the haploinsufficiency of Prep1 is accompanied with a major decrease of Myc-induced apoptosis and that the haploinsufficieny is sufficient for all these effects because the second allele of Prep1 is not lost even at late stages. Therefore, the tumor-suppressive activity