title: PAX5 is a tumor suppressor in mouse mutagenesis models of acute lymphoblastic leukemia.
abstract: Alterations of genes encoding transcriptional regulators of lymphoid development are a hallmark of B-progenitor acute lymphoblastic leukemia (B-ALL) and most commonly involve PAX5, encoding the DNA-binding transcription factor paired-box 5. The majority of PAX5 alterations in ALL are heterozygous, and key PAX5 target genes are expressed in leukemic cells, suggesting that PAX5 may be a haploinsufficient tumor suppressor. To examine the role of PAX5 alterations in leukemogenesis, we performed mutagenesis screens of mice heterozygous for a loss-of-function Pax5 allele. Both chemical and retroviral mutagenesis resulted in a significantly increased penetrance and reduced latency of leukemia, with a shift to B-lymphoid lineage. Genomic profiling identified a high frequency of secondary genomic mutations, deletions, and retroviral insertions targeting B-lymphoid development, including Pax5, and additional genes and pathways mutated in ALL, including tumor suppressors, Ras, and Janus kinase-signal transducer and activator of transcription signaling. These results show that in contrast to simple Pax5 haploinsufficiency, multiple sequential alterations targeting lymphoid development are central to leukemogenesis and contribute to the arrest in lymphoid maturation characteristic of ALL. This cross-species analysis also validates the importance of concomitant alterations of multiple cellular growth, signaling, and tumor suppression pathways in the pathogenesis of B-ALL.
authors: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN;
authors: Jinjun
authors: J
authors: Dang
authors: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN;
authors: Lei
authors: L
authors: Wei
authors: Faculty of Electrical Engineering, Mathematics and Computer Science, Delft Bioinformatics Laboratory, Delft University of Technology, Delft, The Netherlands;
authors: Jeroen
authors: J
authors: de Ridder
authors: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN;
authors: Xiaoping
authors: X
authors: Su
authors: Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom;
authors: Alistair G
authors: AG
authors: Rust
authors: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN;
authors: Kathryn G
authors: KG
authors: Roberts
authors: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN;
authors: Debbie
authors: D
authors: Payne-Turner
authors: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN;
authors: Jinjun
authors: J
authors: Cheng
authors: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN;
authors: Jing
authors: J
authors: Ma
authors: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN; and.
authors: Chunxu
authors: C
authors: Qu
authors: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN; and.
authors: Gang
authors: G
authors: Wu
authors: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN;
authors: Guangchun
authors: G
authors: Song
authors: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN.
authors: Robert G
authors: RG
authors: Huether
authors: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN.
authors: Brenda
authors: B
authors: Schulman
authors: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN;
authors: Laura
authors: L
authors: Janke
authors: Department of Computational Biology, St Jude Children's Research Hospital, Memphis, TN; and.
authors: Jinghui
authors: J
authors: Zhang
authors: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN;
authors: James R
authors: JR
authors: Downing
authors: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN.
authors: Louise
authors: L
authors: van der Weyden
authors: Department of Structural Biology, St Jude Children's Research Hospital, Memphis, TN.
authors: David J
authors: DJ
authors: Adams
authors: Department of Pathology, St Jude Children's Research Hospital, Memphis, TN;
authors: Charles G
authors: http://orcid.org/0000-0002-1871-1850
authors: CG
authors: Mullighan
mesh_terms: D000818:Animals; D017353:Gene Deletion; D051379:Mice; D008817:Mice, Mutant Strains; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051757:PAX5 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051757:PAX5 Transcription Factor; C497282:Pax5 protein, mouse; D025521:Tumor Suppressor Proteins