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Germline Aberrations of PAX5 Cause Susceptibility to pre-B cell Acute Lymphoblastic Leukemia

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 analysis of the PAX5 germline variants demonstrated reduced transcriptional activity, as well as decreased interaction with Groucho-4. 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.

Type: Exome Sequencing
Archiver: European Genome-phenome Archive (EGA)

2 Datasets 12 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001000654	DATA FILES FOR BALL-PAX5	Illumina HiSeq 2000	153
EGAD00001001056	None	Illumina HiSeq 2000	7

Publications	Citations
A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Shah 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 SC, Song G, Cheng J, Meyers P, Bhojwani D, Jhanwar S, Maslak P, Fleisher M, Littman J, Offit L, Rau-Murthy R, Fleischut MH, Corines M, Murali R, Gao X, Manschreck C, Kitzing T, Murty VV, Raimondi S, Kuiper RP, Simons A, Schiffman JD, Onel K, Plon SE, Wheeler D, 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 K, King MC, 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. Nat Genet 45: 2013 1226-1231	237
Germline ETV6 Mutations Confer Susceptibility to Acute Lymphoblastic Leukemia and Thrombocytopenia. Topka S, Vijai J, Walsh MF, Jacobs L, Maria A, Villano D, Gaddam P, Wu G, McGee RB, Quinn E, Inaba H, Hartford C, Pui CH, Pappo A, Edmonson M, Zhang MY, Stepensky P, Steinherz P, Schrader K, Lincoln A, Bussel J, Lipkin SM, Goldgur Y, Harit M, Stadler ZK, Mullighan C, Weintraub M, Shimamura A, Zhang J, Downing JR, Nichols KE, Offit K. PLoS Genet 11: 2015 e1005262	109
PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia. Gu Z, Churchman ML, Roberts KG, Moore I, Zhou X, Nakitandwe J, Hagiwara K, Pelletier S, Gingras S, Berns H, Payne-Turner D, Hill A, Iacobucci I, Shi L, Pounds S, Cheng C, Pei D, Qu C, Newman S, Devidas M, Dai Y, Reshmi SC, Gastier-Foster J, Raetz EA, Borowitz MJ, Wood BL, Carroll WL, Zweidler-McKay PA, Rabin KR, Mattano LA, Maloney KW, Rambaldi A, Spinelli O, Radich JP, Minden MD, Rowe JM, Luger S, Litzow MR, Tallman MS, Racevskis J, Zhang Y, Bhatia R, Kohlschmidt J, Mrózek K, Bloomfield CD, Stock W, Kornblau S, Kantarjian HM, Konopleva M, Evans WE, Jeha S, Pui CH, Yang J, Paietta E, Downing JR, Relling MV, Zhang J, Loh ML, Hunger SP, Mullighan CG. Nat Genet 51: 2019 296-307	463
CICERO: a versatile method for detecting complex and diverse driver fusions using cancer RNA sequencing data. Tian L, Li Y, Edmonson MN, Zhou X, Newman S, McLeod C, Thrasher A, Liu Y, Tang B, Rusch MC, Easton J, Ma J, Davis E, Trull A, Michael JR, Szlachta K, Mullighan C, Baker SJ, Downing JR, Ellison DW, Zhang J. Genome Biol 21: 2020 126	98
Functional interrogation of HOXA9 regulome in MLLr leukemia via reporter-based CRISPR/Cas9 screen. Zhang H, Zhang Y, Zhou X, Wright S, Hyle J, Zhao L, An J, Zhao X, Shao Y, Xu B, Lee HM, Chen T, Zhou Y, Chen X, Lu R, Li C. Elife 9: 2020 e57858	34
Clinical significance of novel subtypes of acute lymphoblastic leukemia in the context of minimal residual disease-directed therapy. Jeha S, Choi J, Roberts KG, Pei D, Coustan-Smith E, Inaba H, Rubnitz JE, Ribeiro RC, Gruber TA, Raimondi SC, Karol SE, Qu C, Brady SW, Gu Z, Yang JJ, Cheng C, Downing JR, Evans WE, Relling MV, Campana D, Mullighan CG, Pui CH. Blood Cancer Discov 2: 2021 326-337	122
Enhancer retargeting of CDX2 and UBTF::ATXN7L3 define a subtype of high-risk B-progenitor acute lymphoblastic leukemia. Kimura S, Montefiori L, Iacobucci I, Zhao Y, Gao Q, Paietta EM, Haferlach C, Laird AD, Mead PE, Gu Z, Stock W, Litzow M, Rowe JM, Luger SM, Hunger SP, Ryland GL, Schmidt B, Ekert PG, Oshlack A, Grimmond SM, Rehn J, Breen J, Yeung D, White DL, Aldoss I, Jabbour EJ, Pui CH, Meggendorfer M, Walter W, Kern W, Haferlach T, Brady S, Zhang J, Roberts KG, Blombery P, Mullighan CG. Blood 139: 2022 3519-3531	44
The genomic landscape of pediatric acute lymphoblastic leukemia. Brady SW, Roberts KG, Gu Z, Shi L, Pounds S, Pei D, Cheng C, Dai Y, Devidas M, Qu C, Hill AN, Payne-Turner D, Ma X, Iacobucci I, Baviskar P, Wei L, Arunachalam S, Hagiwara K, Liu Y, Flasch DA, Liu Y, Parker M, Chen X, Elsayed AH, Pathak O, Li Y, Fan Y, Michael JR, Rusch M, Wilkinson MR, Foy S, Hedges DJ, Newman S, Zhou X, Wang J, Reilly C, Sioson E, Rice SV, Pastor Loyola V, Wu G, Rampersaud E, Reshmi SC, Gastier-Foster J, Guidry Auvil JM, Gesuwan P, Smith MA, Winick N, Carroll AJ, Heerema NA, Harvey RC, Willman CL, Larsen E, Raetz EA, Borowitz MJ, Wood BL, Carroll WL, Zweidler-McKay PA, Rabin KR, Mattano LA, Maloney KW, Winter SS, Burke MJ, Salzer W, Dunsmore KP, Angiolillo AL, Crews KR, Downing JR, Jeha S, Pui CH, Evans WE, Yang JJ, Relling MV, Gerhard DS, Loh ML, Hunger SP, Zhang J, Mullighan CG. Nat Genet 54: 2022 1376-1389	297
Pharmacotypes across the genomic landscape of pediatric acute lymphoblastic leukemia and impact on treatment response. Lee SHR, Yang W, Gocho Y, John A, Rowland L, Smart B, Williams H, Maxwell D, Hunt J, Yang W, Crews KR, Roberts KG, Jeha S, Cheng C, Karol SE, Relling MV, Rosner GL, Inaba H, Mullighan CG, Pui CH, Evans WE, Yang JJ. Nat Med 29: 2023 170-179	76
Prognostic and Pharmacotypic Heterogeneity of Hyperdiploidy in Childhood ALL. Lee SHR, Ashcraft E, Yang W, Roberts KG, Gocho Y, Rowland L, Inaba H, Karol SE, Jeha S, Crews KR, Mullighan CG, Relling MV, Evans WE, Cheng C, Yang JJ, Pui CH. J Clin Oncol 41: 2023 5422-5432	9
Impact of Age on Pharmacogenomics and Treatment Outcomes of B-Cell Acute Lymphoblastic Leukemia. Yoshimura S, Li Z, Gocho Y, Yang W, Crews KR, Lee SHR, Roberts KG, Mullighan CG, Relling MV, Yu J, Yeoh AEJ, Loh ML, Saygin C, Litzow MR, Jeha S, Karol SE, Inaba H, Pui CH, Konopleva M, Jain N, Stock W, Paietta E, Jabbour E, Kornblau SM, Evans WE, Yang JJ. J Clin Oncol 42: 2024 3478-3490	12
Heterogeneity of IKZF1 genomic alterations and risk of relapse in childhood B-cell precursor acute lymphoblastic leukemia. Wang'ondu RW, Ashcraft E, Chang TC, Roberts KG, Brady SW, Fan Y, Evans W, Relling MV, Crews KR, Yang J, Yang W, Pounds S, Wu G, Devidas M, Maloney K, Mattano L, Schore RJ, Angiolillo A, Larsen E, Salzer W, Burke MJ, Loh ML, Jeha S, Pui CH, Inaba H, Cheng C, Mullighan CG. Leukemia 39: 2025 1595-1606	6