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IKAROS deletions dictate a unique gene expression signature in patients with adult B-cell acute lymphoblastic leukemia.

Authors :
Ilaria Iacobucci
Nunzio Iraci
Monica Messina
Annalisa Lonetti
Sabina Chiaretti
Emanuele Valli
Anna Ferrari
Cristina Papayannidis
Francesca Paoloni
Antonella Vitale
Clelia Tiziana Storlazzi
Emanuela Ottaviani
Viviana Guadagnuolo
Sandra Durante
Marco Vignetti
Simona Soverini
Fabrizio Pane
Robin Foà
Michele Baccarani
Markus Müschen
Giovanni Perini
Giovanni Martinelli
Source :
PLoS ONE, Vol 7, Iss 7, p e40934 (2012)
Publication Year :
2012
Publisher :
Public Library of Science (PLoS), 2012.

Abstract

Deletions of IKAROS (IKZF1) frequently occur in B-cell precursor acute lymphoblastic leukemia (B-ALL) but the mechanisms by which they influence pathogenesis are unclear. To address this issue, a cohort of 144 adult B-ALL patients (106 BCR-ABL1-positive and 38 B-ALL negative for known molecular rearrangements) was screened for IKZF1 deletions by single nucleotide polymorphism (SNP) arrays; a sub-cohort of these patients (44%) was then analyzed for gene expression profiling.Total or partial deletions of IKZF1 were more frequent in BCR-ABL1-positive than in BCR-ABL1-negative B-ALL cases (75% vs 58%, respectively, p = 0.04). Comparison of the gene expression signatures of patients carrying IKZF1 deletion vs those without showed a unique signature featured by down-regulation of B-cell lineage and DNA repair genes and up-regulation of genes involved in cell cycle, JAK-STAT signalling and stem cell self-renewal. Through chromatin immunoprecipitation and luciferase reporter assays we corroborated these findings both in vivo and in vitro, showing that Ikaros deleted isoforms lacked the ability to directly regulate a large group of the genes in the signature, such as IGLL1, BLK, EBF1, MSH2, BUB3, ETV6, YES1, CDKN1A (p21), CDKN2C (p18) and MCL1.Here we identified and validated for the first time molecular pathways specifically controlled by IKZF1, shedding light into IKZF1 role in B-ALL pathogenesis.

Subjects

Subjects :
Medicine
Science

Details

Language :
English
ISSN :
19326203
Volume :
7
Issue :
7
Database :
Directory of Open Access Journals
Journal :
PLoS ONE
Publication Type :
Academic Journal
Accession number :
edsdoj.66f4087d20174a9f87d2aaab216b40eb
Document Type :
article
Full Text :
https://doi.org/10.1371/journal.pone.0040934