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

Abstract:

: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.

authors

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

doi

10.1073/pnas.1721678115

subject

Has Abstract

pub_date

2018-10-09 00:00:00

pages

10357-10362

issue

41

eissn

0027-8424

issn

1091-6490

pii

1721678115

journal_volume

115

pub_type

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