PAX5 biallelic genomic alterations define a novel subgroup of B-cell precursor acute lymphoblastic leukemia

Journal article


Publication Details

Author(s): Bastian L, Schroeder MP, Eckert C, Schlee C, Tanchez JO, Kämpf S, Wagner DL, Schulze V, Isaakidis K, Lázaro-Navarro J, Hänzelmann S, James AR, Ekici AB, Burmeister T, Schwartz S, Schrappe M, Horstmann M, Vosberg S, Krebs S, Blum H, Hecht J, Greif PA, Rieger MA, Brüggemann M, Gökbuget N, Neumann M, Baldus CD
Journal: Leukemia
Publication year: 2019
ISSN: 0887-6924


Abstract

Chromosomal rearrangements and specific aneuploidy patterns are initiating events and define subgroups in B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Here we analyzed 250 BCP-ALL cases and identified a novel subgroup (‘PAX5-plus’, n = 19) by distinct DNA methylation and gene expression profiles. All patients in this subgroup harbored mutations in the B-lineage transcription factor PAX5, with p.P80R as hotspot. Mutations either affected two independent codons, consistent with compound heterozygosity, or suffered LOH predominantly through chromosome 9p aberrations. These biallelic events resulted in disruption of PAX5 transcriptional programs regulating B-cell differentiation and tumor suppressor functions. Homozygous CDKN2A/B deletions and RAS-activating hotspot mutations were highly enriched as cooperating events in the genomic profile of PAX5-plus ALL. Together, this defined a specific pattern of triple alterations, exclusive to the novel subgroup. PAX5-plus ALL was observed in pediatric and adult patients. Although restricted by the limited sample size, a tendency for more favorable clinical outcome was observed, with 10 of 12 adult PAX5-plus patients achieving long-term survival. PAX5-plus represents the first BCP-ALL subgroup defined by sequence alterations in contrast to gross chromosomal events and exemplifies how deregulated differentiation (PAX5), impaired cell cycle control (CDKN2A/B) and sustained proliferative signaling (RAS) cooperatively drive leukemogenesis.


FAU Authors / FAU Editors

Ekici, Arif Bülent Dr. rer. nat.
Humangenetisches Institut


External institutions with authors

Barcelona Institute of Science and Technology - BIST
Berliner Institut für Gesundheitsforschung (BIH)
Charité - Universitätsmedizin Berlin
Deutsches Krebsforschungszentrum (DKFZ)
Ludwig-Maximilians-Universität (LMU)
Universitätsklinikum Hamburg-Eppendorf
Universitätsklinikum Schleswig-Holstein (UKSH)


How to cite

APA:
Bastian, L., Schroeder, M.P., Eckert, C., Schlee, C., Tanchez, J.O., Kämpf, S.,... Baldus, C.D. (2019). PAX5 biallelic genomic alterations define a novel subgroup of B-cell precursor acute lymphoblastic leukemia. Leukemia. https://dx.doi.org/10.1038/s41375-019-0430-z

MLA:
Bastian, Lorenz, et al. "PAX5 biallelic genomic alterations define a novel subgroup of B-cell precursor acute lymphoblastic leukemia." Leukemia (2019).

BibTeX: 

Last updated on 2019-26-07 at 16:08