期刊
NATURE GENETICS
卷 45, 期 10, 页码 1226-U179出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.2754
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资金
- Starr Cancer Consortium [I5-A523]
- Robert and Kate Niehaus Clinical Cancer Genetics Initiative
- Sabin Family Research Fund
- Lymphoma Foundation
- Geoffrey Beene Cancer Research Center [78730]
- Sharon Levine Corzine Foundation
- Barbara L. Goldsmith Genetics Research Fund, Cancer Prevention and Research Institute of Texas [RP101089]
- New South Wales Priory of the Knights of the Order of Saint John
- Matthew Bell Foundation
- National Cancer Institute of the US National Institutes of Health (NIH) Comprehensive Cancer Center Core [CA21765]
- American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital
- US NIH [R01DK58161]
- Dutch Cancer Society [KUN2009-4298, KUN2012-5366]
- German Research Foundation [KI1605/1-1]
- National Health and Medical Research Council (NHMRC, Australia)
- Canadian Institutes of Health Research
- National Institute of General Medical Sciences (NIGMS) [T32GM007454]
- NHMRC [APP1023059]
- [APP1024215]
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)(1-3), 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.
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