Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Ikaros Regulates microRNA Networks in Acute Lymphoblastic Leukemia

Version 1 : Received: 15 August 2022 / Approved: 17 August 2022 / Online: 17 August 2022 (11:29:02 CEST)

How to cite: Kogut, S.; Paculova, H.; Rodriguez, P.; Boyd, J.; Richman, A.; Palaria, A.; Schjerven, H.; Frietze, S. Ikaros Regulates microRNA Networks in Acute Lymphoblastic Leukemia. Preprints 2022, 2022080323 (doi: 10.20944/preprints202208.0323.v1). Kogut, S.; Paculova, H.; Rodriguez, P.; Boyd, J.; Richman, A.; Palaria, A.; Schjerven, H.; Frietze, S. Ikaros Regulates microRNA Networks in Acute Lymphoblastic Leukemia. Preprints 2022, 2022080323 (doi: 10.20944/preprints202208.0323.v1).

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 patient-derived IKZF1-mutated B-ALL xenograft-derived 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.

Keywords

miRNA; IKZF1; Acute Lymphoblastic Leukemia

Subject

LIFE SCIENCES, Molecular Biology

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