PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 2018-10, Vol.115 (41), p.10357-10362
• Main Authors: Jamrog, Laura, Chemin, Guillaume, Fregona, Vincent, Coster, Lucie, Pasquet, Marlène, Oudinet, Chloé, Rouquié, Nelly, Prade, Naïs, Lagarde, Stéphanie, Cresson, Charlotte, Hébrard, Sylvie, Huu, Ngoc Sa Nguyen, Bousquet, Marina, Quelen, Cathy, Brousset, Pierre, Mancini, Stéphane J. C., Delabesse, Eric, Khamlichi, Ahmed Amine, Gerby, Bastien, Broccardo, Cyril
• Format: Article
• Language: English
• Subjects: Acute lymphoblastic leukemia; Animals; B-Lymphocytes - pathology; B-Lymphocytes - physiology; Biological Sciences; Cancer; Cell proliferation; Cells; Chromosome translocations; Computer applications; Elastin; Elastin - genetics; Elastin - metabolism; Fusion protein; Gene Expression Regulation, Leukemic; Gene Knock-In Techniques; Genetic transformation; In vivo methods and tests; Janus Kinase 3 - genetics; Leukemia; Life Sciences; Lymphatic leukemia; Lymphocytes B; Mice; Mice, Transgenic; Mutation; Neoplasms, Experimental; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Oncoproteins; Pax5 protein; PAX5 Transcription Factor - genetics; PAX5 Transcription Factor - metabolism; Precursor Cell Lymphoblastic Leukemia-Lymphoma - genetics; Precursor Cell Lymphoblastic Leukemia-Lymphoma - pathology; Protein expression; Protein Tyrosine Phosphatase, Non-Receptor Type 11 - genetics; Proteins; Proto-Oncogene Proteins p21(ras) - genetics; Translocation; Tumor suppressor genes; Tumorigenesis
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1721678115

PAX5 is a well-known haploinsufficient tumor suppressor gene in human B-cell precursor acute lymphoblastic leukemia (B-ALL) and is involved in various chromosomal translocations that fuse a part of PAX5 with other partners. However, the role of PAX5 fusion proteins in B-ALL initiation and transformation is ill-known. We previously reported a new recurrent t(7;9)(q11;p13) chromosomal translocation in human B-ALL that juxtaposed PAX5 to the coding sequence of elastin (ELN). To study the function of the resulting PAX5-ELN fusion protein in B-ALL development, we generated a knockin mouse model in which the PAX5-ELN transgene is expressed specifically in B cells. PAX5-ELN–expressing mice efficiently developed B-ALL with an incidence of 80%. Leukemic transformation was associated with recurrent secondary mutations on Ptpn11, Kras, Pax5, and Jak3 genes affecting key signaling pathways required for cell proliferation. Our functional studies demonstrate that PAX5-ELN affected B-cell development in vitro and in vivo featuring an aberrant expansion of the pro-B cell compartment at the preleukemic stage. Finally, our molecular and computational approaches identified PAX5-ELN–regulated gene candidates that establish the molecular bases of the preleukemic state to drive B-ALL initiation. Hence, our study provides a new in vivo model of human B-ALL and strongly implicates PAX5 fusion proteins as potent oncoproteins in leukemia development.