Ikaros Regulates microRNA Networks in Acute Lymphoblastic Leukemia

Abstract

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.

Leukemogenesis in Acute Lymphoblastic Leukemia through the Lens of Developmental Dynamics of Lymphoid Progenitor Cells: a systematic review

“…Dysregulated Ikaros disrupts these interactions, leading to altered transcription factor activity [23]. For example, impaired Ikaros function may result in the dysregulation of transcription factors involved in lineage commitment and differentiation, such as EBF1, E2A, and NOTCH1, which contributes to the pathogenesis of ALL.…”

The Promising Role of Non-Coding RNAs as Biomarkers and Therapeutic Targets for Leukemia

“…Here, we try to summarize the roles of ncRNAs in leukemia while almost all of them could be considered biomarkers (Table 1). Drug resistance [35] miR-26b PIK3CD [36] miR-26 Ikaros [37] miR-30a NOTCH1 and NOTCH2 [38] miR-221 STAT5 [39] miR-497 CDKN2A/B [40] miR-328 MALAT1 [41] miR-214 ABCB1 [42] miR-10a USF1 [43] miR-203 Proliferation [44] miR-29b Abl-1 [45] miR-320 ABL [46] miR -181a and miR-181b Drug resistance [47,48] miR-125b GRK2 and PUMA [49] lncRNA RP11-137H2. MicroRNAs (miRNAs) are between 19 and 20 nt in length.…”

“…By targeting PIK3CD, the tumor suppressor MiR-26b blocks the PI3K/AKT pathway [36]. PTEN stimulates the expression of miR-26b through the regulation of isoforms of Ikaros [37]. miR-181a contributes to Notch oncogenic signals in T-ALL by lowering Notch negative feedback and enhancing pre-TCR signals [111].…”

MiR-4649-5p acts as a tumor-suppressive microRNA in triple negative breast cancer by direct interaction with PIP5K1C, thereby potentiating growth-inhibitory effects of the AKT inhibitor capivasertib

“…To this end, we selected a still uncharacterized miRNA in breast cancer, called miR-4649-5p, which was detected in a previous study employing an ncRNA microarray screen of spheroids generated from breast cancer cell lines [ 13 ]. This miRNA has recently been associated with prognosis in patients with B-cell acute lymphoblastic leukemia (B-ALL) [ 22 ].…”