title: IKAROS deletions dictate a unique gene expression signature in patients with adult B-cell acute lymphoblastic leukemia.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  Here we identified and validated for the first time molecular pathways specifically controlled by IKZF1, shedding light into IKZF1 role in B-ALL pathogenesis.
authors: Department of Hematology and Oncological Sciences L. and A. Seràgnoli, S. Orsola Malpighi Hospital, University of Bologna, Bologna, Italy.
authors: Ilaria
authors: I
authors: Iacobucci
authors: Nunzio
authors: N
authors: Iraci
authors: Monica
authors: M
authors: Messina
authors: Annalisa
authors: A
authors: Lonetti
authors: Sabina
authors: S
authors: Chiaretti
authors: Emanuele
authors: E
authors: Valli
authors: Anna
authors: A
authors: Ferrari
authors: Cristina
authors: C
authors: Papayannidis
authors: Francesca
authors: F
authors: Paoloni
authors: Antonella
authors: A
authors: Vitale
authors: Clelia Tiziana
authors: CT
authors: Storlazzi
authors: Emanuela
authors: E
authors: Ottaviani
authors: Viviana
authors: V
authors: Guadagnuolo
authors: Sandra
authors: S
authors: Durante
authors: Marco
authors: M
authors: Vignetti
authors: Simona
authors: S
authors: Soverini
authors: Fabrizio
authors: F
authors: Pane
authors: Robin
authors: R
authors: Foà
authors: Michele
authors: M
authors: Baccarani
authors: Markus
authors: M
authors: Müschen
authors: Giovanni
authors: G
authors: Perini
authors: Giovanni
authors: G
authors: Martinelli
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D015331:Cohort Studies; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D051740:Ikaros Transcription Factor; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: C497239:IKZF1 protein, human; D009363:Neoplasm Proteins; D051740:Ikaros Transcription Factor