The hematopoietic
transcription factor Ikaros (IKZF1) regulates normal B cell development and functions as a
tumor suppressor in precursor B cell
acute lymphoblastic leukemia (B-ALL).
MicroRNAs (
miRNAs) are small regulatory RNAs that through post-transcriptional gene regulation play critical roles in intracellular processes including cell growth in
cancer. However, the role of Ikaros in the regulation of
miRNA expression in developing B cells is unknown. In this study, we examined the Ikaros-regulated
miRNA targets using human IKZF1-mutated Ph+ B-ALL cell lines. Inducible expression of wild-type Ikaros (the Ik1
isoform) caused B-ALL growth arrest and exit from the cell cycle. Global
miRNA expression analysis revealed a total of 31
miRNAs regulated by IK1, and ChIP-seq analysis showed that Ikaros bound to several Ik1-responsive
miRNA genes. Examination of the prognostic significance of
miRNA expression in B-ALL indicate that the IK1-regulated
miRNAs hsa-miR-26b, hsa-miR-130b and hsa-miR-4649 are significantly associated with outcome in B-ALL. Our findings establish a potential regulatory circuit between the
tumor-suppressor Ikaros and the oncogenic
miRNA networks in IKZF1-mutated B-ALL. These results indicate that Ikaros regulates the expression of a subset of
miRNAs, of which several may contribute to B-ALL growth.