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

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 (2019)

Publication Type: Journal article

Publication year: 2019

Journal

Leukemia Springer Nature

DOI: 10.1038/s41375-019-0430-z

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.

Authors with CRIS profile

Arif Bülent Ekici Institute of Human Genetics

Involved external institutions

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

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).

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