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Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2018

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

Vincent Fregona
Lucie Coster
  • Fonction : Auteur
Chloé Oudinet
  • Fonction : Auteur
Stéphanie Lagarde
  • Fonction : Auteur
Ngoc Sa Nguyen Huu
  • Fonction : Auteur
Marina Bousquet
Stéphane Mancini
  • Fonction : Auteur

Résumé

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 BALL initiation and transformation is ill-known. We previously reported a new recurrent t(7;9)(q11;p13) chromosomal translocation in human BALL that juxtaposed PAX5 to the coding sequence of elastin (ELN). To study the function of the resulting PAX5-ELN fusion protein in BALL 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 BALL 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 pre-leukemic state to drive BALL initiation. Hence, our study provides a new in vivo model of human BALL and strongly implicates PAX5 fusion proteins as potent oncoproteins in leukemia development.
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Dates et versions

hal-02351122 , version 1 (06-05-2020)

Identifiants

Citer

Laura Jamrog, Guillaume Chemin, Vincent Fregona, Lucie Coster, Marlène Pasquet, et al.. PAX5-ELN oncoprotein promotes multistep B-cell acute lymphoblastic leukemia in mice. Proceedings of the National Academy of Sciences of the United States of America, 2018, 115 (41), pp.10357-10362. ⟨10.1073/pnas.1721678115⟩. ⟨hal-02351122⟩
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