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 Meyers; Deepa 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

doi:10.1038/ng.2754

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

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-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 language	English
Pages (from-to)	1226-1231
Number of pages	6
Journal	Nature Genetics
Volume	45
Issue number	10
DOIs	https://doi.org/10.1038/ng.2754
Publication status	Published - Oct 2013
Externally published	Yes

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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10.1038/ng.2754

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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., ... Offit, K. (2013). A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia. Nature Genetics, 45(10), 1226-1231. https://doi.org/10.1038/ng.2754

@article{9a5893fa67cd401f8f379528a90c6bf8,

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. ",

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

author = "Sohela Shah and Schrader, {Kasmintan A} and Esm{\'e} Waanders and Timms, {Andrew E} and Joseph Vijai and Cornelius Miething and Jeremy Wechsler and Jun Yang and James Hayes and Klein, {Robert J} and Jinghui Zhang and Lei Wei and Gang Wu and Michael Rusch and Panduka Nagahawatte and Jing Ma and Shann-Ching Chen and Guangchun Song and Jinjun Cheng and Paul Meyers and Deepa Bhojwani and Suresh Jhanwar and Peter Maslak and Martin Fleisher and Jason Littman and Lily Offit and Rohini Rau-Murthy and Fleischut, {Megan Harlan} and Marina Corines and Rajmohan Murali and Xiaoni Gao and Christopher Manschreck and Thomas Kitzing and Murty, {Vundavalli V} and Susana Raimondi and Kuiper, {Roland P} and Annet Simons and Schiffman, {Joshua D} and Kenan Onel and Plon, {Sharon E} and David Wheeler and Deborah Ritter and Ziegler, {David S} and Kathy Tucker and Rosemary Sutton and Georgia Chenevix-Trench and Jun Li and Huntsman, {David G} and Samantha Hansford and Janine Senz and Thomas Walsh and Ming Lee and Hahn, {Christopher N} and Kathryn Roberts and Mary-Claire King and Lo, {Sarah M} and Levine, {Ross L} and Agnes Viale and Socci, {Nicholas D} and Nathanson, {Katherine L} and Scott, {Hamish S} and Mark Daly and Lipkin, {Steven M} and Lowe, {Scott W} and Downing, {James R} and David Altshuler and Sandlund, {John T} and Horwitz, {Marshall S} and Mullighan, {Charles G} and Kenneth Offit",

year = "2013",

month = oct,

doi = "10.1038/ng.2754",

language = "English",

volume = "45",

pages = "1226--1231",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "10",

}

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, S-C, 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, 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 2013, 'A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia', Nature Genetics, vol. 45, no. 10, pp. 1226-1231. https://doi.org/10.1038/ng.2754

TY - JOUR

T1 - A recurrent germline PAX5 mutation confers susceptibility to pre-B cell acute lymphoblastic leukemia

AU - Shah, Sohela

AU - Schrader, Kasmintan A

AU - Waanders, Esmé

AU - Timms, Andrew E

AU - Vijai, Joseph

AU - Miething, Cornelius

AU - Wechsler, Jeremy

AU - Yang, Jun

AU - Hayes, James

AU - Klein, Robert J

AU - Zhang, Jinghui

AU - Wei, Lei

AU - Wu, Gang

AU - Rusch, Michael

AU - Nagahawatte, Panduka

AU - Ma, Jing

AU - Chen, Shann-Ching

AU - Song, Guangchun

AU - Cheng, Jinjun

AU - Meyers, Paul

AU - Bhojwani, Deepa

AU - Jhanwar, Suresh

AU - Maslak, Peter

AU - Fleisher, Martin

AU - Littman, Jason

AU - Offit, Lily

AU - Rau-Murthy, Rohini

AU - Fleischut, Megan Harlan

AU - Corines, Marina

AU - Murali, Rajmohan

AU - Gao, Xiaoni

AU - Manschreck, Christopher

AU - Kitzing, Thomas

AU - Murty, Vundavalli V

AU - Raimondi, Susana

AU - Kuiper, Roland P

AU - Simons, Annet

AU - Schiffman, Joshua D

AU - Onel, Kenan

AU - Plon, Sharon E

AU - Wheeler, David

AU - Ritter, Deborah

AU - Ziegler, David S

AU - Tucker, Kathy

AU - Sutton, Rosemary

AU - Chenevix-Trench, Georgia

AU - Li, Jun

AU - Huntsman, David G

AU - Hansford, Samantha

AU - Senz, Janine

AU - Walsh, Thomas

AU - Lee, Ming

AU - Hahn, Christopher N

AU - Roberts, Kathryn

AU - King, Mary-Claire

AU - Lo, Sarah M

AU - Levine, Ross L

AU - Viale, Agnes

AU - Socci, Nicholas D

AU - Nathanson, Katherine L

AU - Scott, Hamish S

AU - Daly, Mark

AU - Lipkin, Steven M

AU - Lowe, Scott W

AU - Downing, James R

AU - Altshuler, David

AU - Sandlund, John T

AU - Horwitz, Marshall S

AU - Mullighan, Charles G

AU - Offit, Kenneth

PY - 2013/10

Y1 - 2013/10

N2 - 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.

AB - 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.

KW - Genetic Predisposition to Disease

KW - Germ-Line Mutation

KW - Humans

KW - PAX5 Transcription Factor/genetics

KW - Polymorphism, Single Nucleotide

KW - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics

U2 - 10.1038/ng.2754

DO - 10.1038/ng.2754

M3 - Article

C2 - 24013638

SN - 1061-4036

VL - 45

SP - 1226

EP - 1231

JO - Nature Genetics

JF - Nature Genetics

IS - 10

ER -

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

Abstract

Keywords

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