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

TitleA recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia.
Publication TypeJournal Article
Year of Publication2013
AuthorsShah, S, Schrader, KA, Waanders, E, Timms, AE, Vijai, J, Miething, C, Wechsler, J, Yang, J, Hayes, J, Klein, RJ, 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, MHarlan, Corines, M, Murali, R, Gao, X, Manschreck, C, Kitzing, T, Murty, VV, Raimondi, SC, Kuiper, RP, Simons, A, Schiffman, JD, Onel, K, Plon, SE, Wheeler, DA, Ritter, D, Ziegler, DS, Tucker, K, Sutton, R, Chenevix-Trench, G, Li, J, Huntsman, DG, Hansford, S, Senz, J, Walsh, T, Lee, M, Hahn, CN, Roberts, KG, King, M-C, Lo, SM, Levine, RL, Viale, A, Socci, ND, Nathanson, KL, Scott, HS, Daly, M, Lipkin, SM, Lowe, SW, Downing, JR, Altshuler, D, Sandlund, JT, Horwitz, MS, Mullighan, CG, Offit, K
JournalNat Genet
Date Published2013 Oct
KeywordsB-Cell-Specific Activator Protein, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Polymorphism, Single Nucleotide, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma

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.

Alternate JournalNat. Genet.
PubMed ID24013638
PubMed Central IDPMC3919799
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
P30 CA021765 / CA / NCI NIH HHS / United States
R01 CA138836 / CA / NCI NIH HHS / United States
R01DK58161 / DK / NIDDK NIH HHS / United States
T32 GM007454 / GM / NIGMS NIH HHS / United States
T32GM007454 / GM / NIGMS NIH HHS / United States
/ / Canadian Institutes of Health Research / Canada