Abstract
BackgroundDeletions 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 FindingsTotal 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.ConclusionsHere we identified and validated for the first time molecular pathways specifically controlled by IKZF1, shedding light into IKZF1 role in B-ALL pathogenesis.
Highlights
Based on cytogenetic and molecular analyses, B-cell precursor acute lymphoblastic leukemia (B-ALL) carries hyperdiploidy, hypodiploidy, translocations t(12;21)[ETV6-RUNX1], t(1;19)[TCF3-PBX1], t(9;22)[BCR-ABL1] and rearrangement of the MLL gene
Our results show that independently from BCR-ABL1, the loss of IKZF1 function dictates a unique expression signature characterized by downregulation of B-cell lineage and DNA repair genes and upregulation of genes involved in cell-cycle progression, JAK/ STAT signalling and stem cell self-renewal, shedding light on the molecular mechanisms that may underlie the leukemogenic potential of Ikaros deletions
single nucleotide polymorphism (SNP) arrays analyses revealed that among the 144 patients tested (Table 1), deletions of IKZF1 occurred in 22 out of 38 (58%) BNEG ALL cases and in 80 out of 106 (75%) adult BCR-ABL1+ cases, indicating that IKZF1 deletion is more frequent in the BCRABL1+ ALL subgroup (p = 0.04)
Summary
Based on cytogenetic and molecular analyses, B-cell precursor acute lymphoblastic leukemia (B-ALL) carries hyperdiploidy, hypodiploidy, translocations t(12;21)[ETV6-RUNX1], t(1;19)[TCF3-PBX1], t(9;22)[BCR-ABL1] and rearrangement of the MLL gene. In B-ALL a high frequency of genetic abnormalities in key pathways, including lymphoid differentiation, cell cycle regulation, tumor suppression, and drug responsiveness, have been identified [9,10] Among these abnormalities, deletions of IKZF1 gene, encoding the transcription factor Ikaros, were found in about 28% of pediatric BCR-ABL1 negative ALL cases and in more than 80% of adult BCR-ABL1 positive cases [7,11]. The precise mechanism(s) by which Ikaros alterations contribute to leukemogenesis and worse prognosis have not yet been clearly defined To investigate this aspect, we correlated the genomic status of the IKZF1 gene in a cohort of adult B-ALL patients (BCR-ABL1 positive and B-ALL negative for known molecular rearrangements, here named B-NEG, cases) with transcription profiles.
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