PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice
Menée notamment à l'aide d'un modèle murin de leucémie aiguë lymphoblastique de type B, cette étude française met en évidence des mécanismes par lesquels la protéine issue de la fusion des gènes PAX5 et ELN favorise le développement de la maladie
Engineered mouse models of acute leukemia are critical to understanding the biological mechanisms by which a primary oncogene induces disease. While PAX5 fusion proteins are considered primary oncogenic events in B-ALL, their role in leukemia development is ill-known due to the lack of animal models. This report provides a novel and accurate in vivo model for B-ALL induced by PAX5-ELN fusion protein that establishes a preleukemic phase and recapitulates the key features of human disease, including acquired mutations in genes of the JAK/STAT and RAS/MAPK pathways. This study is of general interest, as it allows a better understanding of the biological mechanism by which an oncoprotein perturbs normal B-cell development and leads to pathological B-ALL.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.