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


Authors: Shah, S.; Schrader, K. A.; Waanders, E.; Timms, A. E.; Vijai, J.; Miething, C.; Wechsler, J.; Yang, J.; Hayes, J.; Klein, R. J.; Zhang, J.; Wei, L.; Wu, G.; Rusch, M.; Nagahawatte, P.; Ma, J.; Chen, S. C.; Song, G.; Cheng, J.; Meyers, P.; Bhojwani, D.; Jhanwar, S.; Maslak, P.; Fleisher, M.; Littman, J.; Offit, L.; Rau-Murthy, R.; Fleischut, M. H.; Corines, M.; Murali, R.; Gao, X.; Manschreck, C.; Kitzing, T.; Murty, V. V.; Raimondi, S. C.; Kuiper, R. P.; Simons, A.; Schiffman, J. D.; Onel, K.; Plon, S. E.; Wheeler, D. A.; Ritter, D.; Ziegler, D. S.; Tucker, K.; Sutton, R.; Chenevix-Trench, G.; Li, J.; Huntsman, D. G.; Hansford, S.; Senz, J.; Walsh, T.; Lee, M.; Hahn, C. N.; Roberts, K. G.; King, M. C.; Lo, S. M.; Levine, R. L.; Viale, A.; Socci, N. D.; Nathanson, K. L.; Scott, H. S.; Daly, M.; Lipkin, S. M.; Lowe, S. W.; Downing, J. R.; Altshuler, D.; Sandlund, J. T.; Horwitz, M. S.; Mullighan, C. G.; Offit, K.
Article 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. © 2013 Nature America, Inc. All rights reserved.
Journal Title: Nature Genetics
Volume: 45
Issue: 10
ISSN: 1061-4036
Publisher: Nature Publishing Group  
Date Published: 2013-10-01
Start Page: 1226
End Page: 1231
Language: English
DOI: 10.1038/ng.2754
PROVIDER: scopus
PUBMED: 24013638
PMCID: PMC3919799
DOI/URL:
Notes: --- - Cited By (since 1996):2 - "Export Date: 1 November 2013" - "CODEN: NGENE" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Kenneth Offit
    519 Offit
  2. Ross Levine
    490 Levine
  3. Agnes Viale
    205 Viale
  4. Rajmohan Murali
    157 Murali
  5. Peter Maslak
    168 Maslak
  6. Nicholas D Socci
    188 Socci
  7. Robert J. Klein
    60 Klein
  8. Vijai Joseph
    120 Joseph
  9. Sohela Shah
    15 Shah
  10. Martin Fleisher
    242 Fleisher
  11. Paul Meyers
    247 Meyers
  12. Suresh C Jhanwar
    217 Jhanwar
  13. Scott W Lowe
    149 Lowe
  14. James E Hayes
    6 Hayes
  15. Xiaoni Gao
    2 Gao
  16. Marina Julia Corines
    13 Corines
  17. Lily Rosalind Offit
    3 Offit