| First Author | Jamrog L | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 41 | Pages | 10357-10362 |
| PubMed ID | 30257940 | Mgi Jnum | J:266607 |
| Mgi Id | MGI:6202881 | Doi | 10.1073/pnas.1721678115 |
| Citation | Jamrog L, et al. (2018) PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice. Proc Natl Acad Sci U S A 115(41):10357-10362 |
| abstractText | 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. |
