Abstract 2620: Global epigenetic regulation of gene expression and tumor suppression in T-cell leukemia by Ikaros

Abstract

Ikaros encodes a DNA-binding zinc finger protein that functions as a tumor suppressor. Loss of Ikaros function results in the development of high-risk B-cell and T-cell acute lymphoblastic leukemia. Previous studies suggested that Ikaros controls expression of its target genes via chromatin remodeling, and by forming complexes with the histone deacetylase, HDAC1. However, the mechanisms through which Ikaros regulates the global epigenetic signature in leukemia is unknown. We studied the role of Ikaros in regulating tumor suppression in Ikaros-defficient T-cell acute lymphoblastic leukemia (T-ALL) cells. The re-introduction of Ikaros at physiological levels via retroviral transduction into T-ALL cells, results in a cessation of cellular proliferation and cell cycle arrest within 4 days. To determine the dynamics of Ikaros-mediated epigenetic regulation of gene expression in T-ALL, we performed ChIP-seq of Ikaros, HDAC1, and histone modifications, along with microarray and ATAC-seq in wild-type T-ALL (that lacks Ikaros), and during each of 3 days following the re-introduction of Ikaros. Our results demonstrated that Ikaros directly regulates the global epigenomic landscape including genome wide de novo formation of enhancers in T-ALL. Further analysis showed that Ikaros induces the re-distribution of HDAC1 via direct recruitment of HDAC1 to promoter and enhancer regions of different target genes resulting in their transcriptional repression. Expression analysis identified a large number of novel signaling pathways that are directly regulated by Ikaros and HDAC1, and are responsible for the cessation of proliferation and the cell cycle arrest of T-ALL cells. Our results identified novel functions of Ikaros in the epigenetic regulation of gene expression and tumor suppression in T-ALL. Citation Format: Yali Ding, Bo Zhang, Jonathon L. Payne, Kimberly J. Payne, Chunhua Song, Chandrika Gowda, Soumya Iyer, Pavan K. Dhanyamraju, Dhimant Desai, Suming Huang, Feng Yue, Sinisa Dovat. Global epigenetic regulation of gene expression and tumor suppression in T-cell leukemia by Ikaros [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2620.