title: Molecular role of the PAX5-ETV6 oncoprotein in promoting B-cell acute lymphoblastic leukemia.
abstract: PAX5 is a tumor suppressor in B-ALL, while the role of PAX5 fusion proteins in B-ALL development is largely unknown. Here, we studied the function of PAX5-ETV6 and PAX5-FOXP1 in mice expressing these proteins from thePax5locus. Both proteins arrested B-lymphopoiesis at the pro-B to pre-B-cell transition and, contrary to their proposed dominant-negative role, did not interfere with the expression of most regulated Pax5 target genes. Pax5-Etv6, but not Pax5-Foxp1, cooperated with loss of the Cdkna2a/b tumor suppressors in promoting B-ALL development. Regulated Pax5-Etv6 target genes identified in these B-ALLs encode proteins implicated in pre-B-cell receptor (BCR) signaling and migration/adhesion, which could contribute to the proliferation, survival, and tissue infiltration of leukemic B cells. Together with similar observations made in human PAX5-ETV6+B-ALLs, these data identified PAX5-ETV6 as a potent oncoprotein that drives B-cell leukemia development.
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Leonie
authors.initials: L
authors.lastname: Smeenk
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Maria
authors.initials: M
authors.lastname: Fischer
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Jurado
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Jaritz
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Anna
authors.initials: A
authors.lastname: Azaryan
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Werner
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Mareike
authors.initials: M
authors.lastname: Roth
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zuber
authors.affiliation: Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Stanulla
authors.affiliation: Department of Pediatric Oncology and Hematology, Erasmus Medical Center, Sophia Children Hospital, Rotterdam, The Netherlands.
authors.forename: Monique L
authors.initials: ML
authors.lastname: den Boer
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, TN, USA.
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.affiliation: Children's Cancer Research Institute, St. Anna Kinderkrebsforschung e.V., Vienna, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Strehl
authors.affiliation: Research Institute of Molecular Pathology (IMP), Vienna Biocenter (VBC), Vienna, Austria busslinger@imp.ac.at.
authors.forename: Meinrad
authors.identifier: 0000-0002-9111-9351
authors.initials: M
authors.lastname: Busslinger
mesh_terms: D000818:Animals; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D051379:Mice; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000473:pathology*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D051858:Forkhead Transcription Factors; D015513:Oncogene Proteins; D051757:PAX5 Transcription Factor; D050783:Proto-Oncogene Proteins c-ets; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D000097764:ETS Translocation Variant 6 Protein; C432917:Foxp1 protein, mouse; C497282:Pax5 protein, mouse
keywords: B‐cell leukemia; CDKN2A/B cooperation; PAX5‐ETV6; mouse model; regulated target genes