title: Reduction of Prep1 levels affects differentiation of normal and malignant B cells and accelerates Myc driven lymphomagenesis.
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 EμMyc 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 EμMyc-Prep1(+/-) mice are much more immature, being mostly made up of Pro-B or Pre-B cells, while those in the EμMyc-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 EμMyc 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 of Prep1 is intertwined with both the interference with Myc-induced apoptosis as well as with natural developmental functions of the protein.
authors.affiliation: Laboratory of Transcriptional Regulation in Development and Cancer, Fondazione Istituto FIRC di Oncologia Molecolare, Milano, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Iotti
authors.forename: Stefania
authors.initials: S
authors.lastname: Mejetta
authors.forename: Livia
authors.initials: L
authors.lastname: Modica
authors.forename: Dmitry
authors.initials: D
authors.lastname: Penkov
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.forename: Francesco
authors.initials: F
authors.lastname: Blasi
mesh_terms: D000483:Alleles; D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D049109:Cell Proliferation; D005434:Flow Cytometry / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D057895:Haploinsufficiency; D018398:Homeodomain Proteins / Q000378:metabolism*; D016130:Immunophenotyping; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D019656:Loss of Heterozygosity; D008214:Lymphocytes / Q000166:cytology; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods
chemical_list: D018398:Homeodomain Proteins; C491412:Pknox1 protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D017493:Leukocyte Common Antigens