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10 2018 Proceedings of the National Academy of Sciences of the United States of America

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


Jamrog L, Chemin G, Fregona V, Coster L, Pasquet M, Oudinet C, Rouquié N, Prade N, Lagarde S, Cresson C, Hébrard S, Nguyen Huu NS, Bousquet M, Quelen C, Brousset P, Mancini SJC, Delabesse E, Khamlichi AA, Gerby B, Broccardo C


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 to the coding sequence of elastin (). To study the function of the resulting PAX5-ELN fusion protein in B-ALL development, we generated a knockin mouse model in which the 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 , , , and 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.

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