E-GEOD-45834 - Germline Aberrations of PAX5 Cause Susceptibility to pre-B cell Acute Lymphoblastic Leukemia
Released on 6 April 2014, last updated on 10 July 2015
A novel heterozygous germline variant, c.547G>A (p.Gly183Ser), in the paired box protein encoding gene, PAX5, was found to segregate with disease in two unrelated kindreds with autosomal dominant pre-B cell acute lymphoblastic leukemia (ALL). Leukemic cells from 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 demonstrated PAX5 Gly183 substitution in the leukemic cells. Functional and gene expression analysis of the PAX5 germline variants demonstrated reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B ALL, and implicate PAX5 in a novel syndrome of germline susceptibility to pre-B cell neoplasia. We analyzed 10 samples of J558 murine myeloma cells infected with MSCV-Puro-IRES-GFP (PIG) empty vector (EV; three independent replicates), MSCV-PIG Pax5 WT (WT; three independent replicates), and MSCV-PIG Pax5 G183S (Mut; four independent replicates). Cells were selected with puromycin after infection for 5-7 days, subsequently cells were sorted for GFP and IgM expression by FACS.
transcription profiling by array
Shann-Ching Chen <Shann-Ching.Chen@stjude.org>, Agnes Viale, Andrew E Timms, Annet Simons, Charles G Mullighan, Christopher Manschreck, Christopher N Hahn, Cornelius Miething, David Altshuler, David G Huntsman, David S Ziegler, David Wheeler, Deborah Ritter, Deepa Bhojwani, Esm√© Waanders, Gang Wu, Georgia Chenevix-Trench, Guangchun Song, Hamish S Scott, James Downing, James Hayes, Janine Senz, Jason Littman, Jeremy Wechsler, Jing Ma, Jinghui Zhang, John T Sandlund, Joseph Vijai, Joshua D Schiffman, Jun Li, Jun Yang, Kasmintan A Schrader, Katherine L Nathanson, Kathy Tucker, Kenan Onel, Kenneth Offit, Lei Wei, Lily Offit, Mark Daly, Marshall S Horwitz, Martin Fleisher, Mary-Claire King, Megan Harlan-Fleischut, Mike Rusch, Ming Lee, Nicholas D Socci, Panduka Nagahawatte, Paul Meyers, Peter Maslak, Robert J Klein, Rohini Rau-Murthy, Roland P Kuiper, Rosemary Sutton, Ross L Levine, Samantha Hansford, Sarah M Lo, Scott W Lowe, Sharon E Plon, Sohela Shah, Steven M Lipkin, Suresh Jhanwar, Susana Raimondi, Thomas Kitzing, Tom Walsh, Vundavalli V Murty, Xiaoni Gao