The PAX5 gene is frequently rearranged in BCR-ABL1-positive acute lymphoblastic leukemia but is not associated with outcome. A report on behalf of the GIMEMA Acute Leukemia Working Party.
BACKGROUND
Recently, in genome-wide analyses of DNA copy number abnormalities using single nucleotide polymorphism microarrays, genetic alterations targeting PAX5 were identified in over 30% of pediatric patients with acute lymphoblastic leukemia. So far the occurrence of PAX5 alterations and their clinical correlation have not been investigated in adults with BCR-ABL1-positive acute lymphoblastic leukemia.


METHODS
The aim of this study was to characterize the rearrangements on 9p involving PAX5 and their clinical significance in adults with BCR-ABL1-positive acute lymphoblastic leukemia. Eighty-nine adults with de novo BCR-ABL1-positive acute lymphoblastic leukemia were enrolled into institutional (n=15) or GIMEMA (Gruppo Italiano Malattie EMatologiche dell'Adulto) (n=74) clinical trials and, after obtaining informed consent, their genome was analyzed by single nucleotide polymorphism arrays (Affymetrix 250K NspI and SNP 6.0), genomic polymerase chain reaction analysis and re-sequencing.


RESULTS
PAX5 genomic deletions were identified in 29 patients (33%) with the extent of deletions ranging from a complete loss of chromosome 9 to the loss of a subset of exons. In contrast to BCR-ABL1-negative acute lymphoblastic leukemia, no point mutations were found, suggesting that deletions are the main mechanism of inactivation of PAX5 in BCR-ABL1-positive acute lymphoblastic leukemia. The deletions were predicted to result in PAX5 haploinsufficiency or expression of PAX5 isoforms with impaired DNA-binding. Deletions of PAX5 were not significantly correlated with overall survival, disease-free survival or cumulative incidence of relapse, suggesting that PAX5 deletions are not associated with outcome.


CONCLUSIONS
PAX5 deletions are frequent in adult BCR-ABL1-positive acute lymphoblastic leukemia and are not associated with a poor outcome.
Iacobucci
Ilaria
I
Molecular Biology Unit, Department of Hematology/Oncology Seràgnoli, University of Bologna, Via Massarenti 9, Bologna, Italy.
Lonetti
Annalisa
A
Paoloni
Francesca
F
Papayannidis
Cristina
C
Ferrari
Anna
A
Storlazzi
Clelia Tiziana
CT
Vignetti
Marco
M
Cilloni
Daniela
D
Messa
Francesca
F
Guadagnuolo
Viviana
V
Paolini
Stefania
S
Elia
Loredana
L
Messina
Monica
M
Vitale
Antonella
A
Meloni
Giovanna
G
Soverini
Simona
S
Pane
Fabrizio
F
Baccarani
Michele
M
Foà
Robin
R
Martinelli
Giovanni
G
D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D016044:Fusion Proteins, bcr-abl / Q000235:genetics; D017353:Gene Deletion; D015321:Gene Rearrangement; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D051757:PAX5 Transcription Factor / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000175:diagnosis / Q000235:genetics*; D011379:Prognosis
D051757:PAX5 Transcription Factor; C497281:PAX5 protein, human; D016044:Fusion Proteins, bcr-abl