title: A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia.
abstract: Somatic alterations of the lymphoid transcription factor gene PAX5 (also known as BSAP) are a hallmark of B cell precursor acute lymphoblastic leukemia (B-ALL), but inherited mutations of PAX5 have not previously been described. Here we report a new heterozygous germline variant, c.547G>A (p.Gly183Ser), affecting the octapeptide domain of PAX5 that was found to segregate with disease in two unrelated kindreds with autosomal dominant B-ALL. Leukemic cells from all affected individuals in both families exhibited 9p deletion, with loss of heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss harbored somatic PAX5 substitutions affecting Gly183. Functional and gene expression analysis of the PAX5 mutation demonstrated that it had significantly reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B cell ALL and implicate PAX5 in a new syndrome of susceptibility to pre-B cell neoplasia.
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.|Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Sohela
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authors.lastname: Shah
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.|Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Kasmintan A
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authors.lastname: Schrader
authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Radboud Institute for Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
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authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
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authors.lastname: Timms
authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.|Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
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authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
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authors.affiliation: Department of Pathology, University of Washington, Seattle, Washington, USA.
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authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
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authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.|Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
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authors.affiliation: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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authors.affiliation: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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authors.affiliation: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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authors.affiliation: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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authors.affiliation: Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.|Pediatric Cancer Genome Project Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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authors.initials: VV
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authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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authors.affiliation: Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
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authors.affiliation: Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.|Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
authors.forename: Kenneth
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mesh_terms: D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D051757:PAX5 Transcription Factor / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*
chemical_list: D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human