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

Sohela Shah, Kasmintan A Schrader, Esmé Waanders, Andrew E Timms, Joseph Vijai, Cornelius Miething, Jeremy Wechsler, Jun Yang, James Hayes, Robert J Klein, Jinghui Zhang, Lei Wei, Gang Wu, Michael Rusch, Panduka Nagahawatte, Jing Ma, Shann-Ching Chen, Guangchun Song, Jinjun Cheng, Paul MeyersDeepa Bhojwani, Suresh Jhanwar, Peter Maslak, Martin Fleisher, Jason Littman, Lily Offit, Rohini Rau-Murthy, Megan Harlan Fleischut, Marina Corines, Rajmohan Murali, Xiaoni Gao, Christopher Manschreck, Thomas Kitzing, Vundavalli V Murty, Susana Raimondi, Roland P Kuiper, Annet Simons, Joshua D Schiffman, Kenan Onel, Sharon E Plon, David Wheeler, Deborah Ritter, David S Ziegler, Kathy Tucker, Rosemary Sutton, Georgia Chenevix-Trench, Jun Li, David G Huntsman, Samantha Hansford, Janine Senz, Thomas Walsh, Ming Lee, Christopher N Hahn, Kathryn Roberts, Mary-Claire King, Sarah M Lo, Ross L Levine, Agnes Viale, Nicholas D Socci, Katherine L Nathanson, Hamish S Scott, Mark Daly, Steven M Lipkin, Scott W Lowe, James R Downing, David Altshuler, John T Sandlund, Marshall S Horwitz, Charles G Mullighan, Kenneth Offit

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1226-1231
Number of pages6
JournalNature Genetics
Volume45
Issue number10
DOIs
Publication statusPublished - Oct 2013
Externally publishedYes

Keywords

  • Genetic Predisposition to Disease
  • Germ-Line Mutation
  • Humans
  • PAX5 Transcription Factor/genetics
  • Polymorphism, Single Nucleotide
  • Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics

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