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)1,2,3, 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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Acknowledgements
We thank M.A.S. Moore and S. Jae-Hung for their contributions to ongoing tumor studies (Sloan-Kettering Institute); G. Dressler (University of Michigan) for the mouse GRG4 construct; M. Busslinger (The Research Institute for Molecular Pathology) for the luc-CD19 reporter construct; J. Hagman (National Jewish) for providing a PAX5 vector and the J558LμM cell line; D. Payne-Turner (St. Jude Children's Research Hospital) for technical assistance; W. Yang and C. Smith (Pharmaceutical Sciences, St. Jude Children's Research Hospital) for their assistance in the haplotype analyses; and the Tissue Resources Core Facility, Pediatric Cancer Genome Project Core Facility and Flow Cytometry and Cell Sorting Core Facility of St. Jude Children's Research Hospital. We thank the families for their generous participation in these studies. This project was supported by grant I5-A523 from the Starr Cancer Consortium, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, the Sabin Family Research Fund, the Lymphoma Foundation, Geoffrey Beene Cancer Research Center grant 78730, the Sharon Levine Corzine Foundation, the Barbara L. Goldsmith Genetics Research Fund, Cancer Prevention and Research Institute of Texas grant RP101089, the New South Wales Priory of the Knights of the Order of Saint John, the Matthew Bell Foundation, National Cancer Institute of the US National Institutes of Health (NIH) Comprehensive Cancer Center Core grant CA21765, the American Lebanese Syrian Associated Charities of St. Jude Children's Research Hospital and grant R01DK58161 from the US NIH. R.P.K. is funded by a grant from the Dutch Cancer Society (KUN2009-4298). T.K. is supported by a German Research Foundation Postdoctoral Fellowship (KI1605/1-1). C.G.M. is a Pew Scholar in the Biomedical Sciences and a St. Baldrick's Scholar. K.G.R. is supported by a National Health and Medical Research Council (NHMRC, Australia) CJ Martin Postdoctoral Fellowship. K.A.S. is funded by the Canadian Institutes of Health Research. A.E.T. is supported by T32GM007454 from the National Institute of General Medical Sciences (NIGMS). G.C.-T. is a Senior Principal Research Fellow of the NHMRC. E.W. is funded by the Dutch Cancer Society, project number KUN2012-5366. H.S.S. is a Principal Research Fellow of the NHMRC (APP1023059), and the work was supported by grant APP1024215.
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K. Offit, C.G.M., M.S.H., J.T.S., S.S., K.A.S., E.W., A.E.T., J.V., C. Miething, S.M. Lipkin, R.J.K., M.D., D.A. and S.W.L. conceived and designed the experiment. S.S., K.A.S., E.W., A.E.T., J.V., C. Miething, J.W., J.Y., X.G., C. Manschreck, R.J.K., A.V., N.D.S., D.A., M.S.H., C.G.M., K. Offit, M.-C.K., T.W., M.L., T.K., D.B., J. Littman, L.O., S.C.R., P. Maslak, M.F., K.G.R. and J.C. performed the experiments. S.S., K.A.S., E.W., A.E.T., J.V., C. Miething, J.W., J.Y., R.J.K., N.D.S., M.S.H., C.G.M., K. Offit, L.W., J.Z., G.W., M.R., P.N., J.M., S.-C.C., G.S. and J.C. performed statistical analysis. S.S., K.A.S., E.W., A.E.T., J.V., C. Miething, J.W., J.Y., C. Manschreck, R.R.-M., M.C., R.M., M.H.F., S.M. Lipkin, R.J.K., A.V., N.D.S., D.A., C.N.H., H.S.S., S.W.L., M.S.H., C.G.M., K. Offit, L.W., J.H., J.Z., G.W., M.R., P.N., J.M., S.-C.C., G.S. and J.C. analyzed the data. E.W., C. Miething, J.T.S., S.J., M.H.F., J.S., V.V.M., S.E.P., D.G.H., D.S.Z., G.C.-T., S.M. Lipkin, S.M. Lo, R.L.L., A.V., K.L.N., M.D., D.A., C.N.H., H.S.S., S.W.L., M.S.H., C.G.M., K. Onel, R.P.K., A.S., J. Li, K.T., R.S., S.H., J.D.S., D.A.W., D.R., P. Meyers, J.Z., G.W., J.M., S.-C.C., J.R.D. and K. Offit contributed reagents, materials and analysis tools. K. Offit, C.G.M., M.S.H., S.S., K.A.S., E.W., A.E.T., J.V., C. Miething, J.Y., R.J.K. and S.W.L. wrote the manuscript. K. Offit, C.G.M., M.S.H., J.T.S., R.J.K., M.D., D.A. and S.W.L. jointly supervised the research.
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Supplementary information
Supplementary Text and Figures
Supplementary Note, Supplementary Figures 1–8 and Supplementary Tables 1–8 and 13–15 (PDF 1509 kb)
Supplementary Table 9
Expression of somatic SNVs in family 2 (XLSX 19 kb)
Supplementary Table 10
Expression of shared germline SNVs in family 2 (XLSX 11 kb)
Supplementary Table 11
Expression of germline SNVs of family 2 IV2 (XLSX 31 kb)
Supplementary Table 12
Expression of germline SNVs of family 2 IV1 (XLSX 35 kb)
Supplementary Table 16
RNASeq data from human ALL samples. (XLS 518 kb)
Supplementary Table 17
Mouse expression array data from J558LμM transduced cells, WT vs MT (XLS 1114 kb)
Supplementary Table 18
Mouse expression array data from J558LμM transduced cells, MIR vs MT (XLS 1245 kb)
Supplementary Table 19
PAX5 p.Gly183Ser signature in familial ALL (XLSX 14146 kb)
Supplementary Table 20
PAX5 signature in ETV6-RUNX1 ALL (XLSX 9454 kb)
Supplementary Table 21
Expression analyses gene sets (XLSX 42 kb)
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Shah, S., Schrader, K., Waanders, E. et al. A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Nat Genet 45, 1226–1231 (2013). https://doi.org/10.1038/ng.2754
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DOI: https://doi.org/10.1038/ng.2754
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