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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.    Principal Findings  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.

IKAROS Deletions Dictate a Unique Gene Expression Signature in Patients with Adult B-Cell Acute Lymphoblastic Leukemia