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Nat Genet. 2013 Oct;45(10):1226-1231. doi: 10.1038/ng.2754. Epub 2013 Sep 8.

A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia.

Author information

1
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
2
Clinical Genetics Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
3
Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
4
Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences and Radboud Institute for Oncology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
5
Department of Pathology, University of Washington, Seattle, Washington, USA.
6
Department of Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
7
Department of Computational Biology and Bioinformatics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
8
Pediatric Cancer Genome Project Laboratory, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
9
Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
10
Department of Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
11
Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
12
Hematology Laboratory Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
13
Clinical Chemistry Service, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
14
Department of Pathology and Cell Biology, Columbia University, New York, New York, USA.
15
High Risk Pediatric Cancer Clinic, Huntsman Cancer Institute/Primary Children's Medical Center, University of Utah, Salt Lake City, Utah, USA.
16
Pediatrics, University of Chicago, Chicago, IL , USA.
17
Texas Children's Cancer Center and Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, USA.
18
Kids Cancer Centre, Sydney Children's Hospital, Sydney, New South Wales, Australia, Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, University of New South Wales, Sydney, New South Wales, Australia.
19
Hereditary Cancer Clinic Prince of Wales Hospital, Randwick, Australia.
20
Children's Cancer Institute Australia for Medical Research, University of New South Wales, Randwick, Australia.
21
Cancer Genetics Laboratory, The Queensland Institute of Medical Research, Herston, Australia.
22
Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
23
Departments of Medicine and Genome Sciences, University of Washington, Seattle, Washington, USA.
24
Department of Molecular Pathology, SA Pathology and Centre for Cancer Biology, Adelaide, Australia.
25
Department of Pediatrics, Weill Cornell College of Medicine, New York, New York, USA.
26
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
27
Genomics Core Laboratory, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
28
Bioinformatics Core, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
29
Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
30
Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.
31
Department of Medicine, Weill Cornell College of Medicine, New York, New York, USA.
#
Contributed equally

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.

PMID:
24013638
PMCID:
PMC3919799
DOI:
10.1038/ng.2754
[Indexed for MEDLINE]
Free PMC Article

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