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.
journal_name
Proc Natl Acad Sci U S Aauthors
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 Cdoi
10.1073/pnas.1721678115subject
Has Abstractpub_date
2018-10-09 00:00:00pages
10357-10362issue
41eissn
0027-8424issn
1091-6490pii
1721678115journal_volume
115pub_type
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