Critical roles of IKAROS and HDAC1 in regulation of heterochromatin and tumor suppression in T-cell acute lymphoblastic leukemia

The IKZF1 gene encodes IKAROS - a DNA binding protein that acts as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). IKAROS can act as a transcriptional repressor via recruitment of histone deacetylase 1 (HDAC1) and chromatin remodeling, however the mechanisms through which IKAROS exerts its tumor suppressor function via heterochromatin in T-ALL are largely unknown. We studied human and mouse T-ALL using a loss-of-function and IKZF1 re-expression approach, along with primary human T-ALL, and normal human and mouse thymocytes to establish the role of IKAROS and HDAC1 in global regulation of facultative heterochromatin and transcriptional repression in T-ALL. Results identified novel IKAROS and HDAC1 functions in T-ALL: Both IKAROS and HDAC1 are essential for EZH2 histone methyltransferase activity and formation of facultative heterochromatin; recruitment of HDAC1 by IKAROS is critical for establishment of H3K27me3 histone modification and repression of active enhancers; and IKAROS-HDAC1 complexes promote formation and expansion of H3K27me3 Large Organized Chromatin lysine (K) domains (LOCKs) and Broad Genic Repression Domains (BGRDs) in T-ALL. Our results establish the central role of IKAROS and HDAC1 in activation of EZH2, global regulation of the facultative heterochromatin landscape, and silencing of active enhancers that regulate oncogene expression.

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Publication Details

Journal
Leukemia
Published
2025-06-24
DOI
https://doi.org/10.1038/s41375-025-02651-1
Citations
1
Primary Topic
Acute Lymphoblastic Leukemia research
Type
article
Field-Weighted Citation Impact
1.88

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Critical roles of IKAROS and HDAC1 in regulation of heterochromatin and tumor suppression in T-cell acute lymphoblastic leukemia

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Critical roles of IKAROS and HDAC1 in regulation of heterochromatin and tumor suppression in T-cell acute lymphoblastic leukemia

Chingakham Ranjit Singh, Katarina Dovat, Yali Ding, Joseph Schramm, Jeremy A. Hengst, James R. Broach, Feng Yue, Daniel Bogush, Charyguly Annageldiyev, Vladimir S. Spiegelman, Glenn Dorsam, Chi T. Viet, Sinisa Dovat, Diwakar Bastihalli Tukaramrao, Dhimant Desai, Avinash K. Kudva, Julia Randazzo, Suming Huang, Arati Sharma, Bing He, Giselle Saulnier Scholler
article en
1 citations

Abstract

The IKZF1 gene encodes IKAROS - a DNA binding protein that acts as a tumor suppressor in T-cell acute lymphoblastic leukemia (T-ALL). IKAROS can act as a transcriptional repressor via recruitment of histone deacetylase 1 (HDAC1) and chromatin remodeling, however the mechanisms through which IKAROS exerts its tumor suppressor function via heterochromatin in T-ALL are largely unknown. We studied human and mouse T-ALL using a loss-of-function and IKZF1 re-expression approach, along with primary human T-ALL, and normal human and mouse thymocytes to establish the role of IKAROS and HDAC1 in global regulation of facultative heterochromatin and transcriptional repression in T-ALL. Results identified novel IKAROS and HDAC1 functions in T-ALL: Both IKAROS and HDAC1 are essential for EZH2 histone methyltransferase activity and formation of facultative heterochromatin; recruitment of HDAC1 by IKAROS is critical for establishment of H3K27me3 histone modification and repression of active enhancers; and IKAROS-HDAC1 complexes promote formation and expansion of H3K27me3 Large Organized Chromatin lysine (K) domains (LOCKs) and Broad Genic Repression Domains (BGRDs) in T-ALL. Our results establish the central role of IKAROS and HDAC1 in activation of EZH2, global regulation of the facultative heterochromatin landscape, and silencing of active enhancers that regulate oncogene expression.

LeukemiaVol. 39(8)
Northwestern University (US), Pennsylvania State University (US), Loma Linda University (US), North Dakota State University (US), Penn State Milton S. Hershey Medical Center (US)
Pennsylvania State University, Four Diamonds, Penn State College of Medicine, National Human Genome Research Institute, National Cancer Institute, National Institute of General Medical Sciences, Hyundai Hope On Wheels
Good health and well-being
Openalex Percentile: Top 15%
Acute Lymphoblastic Leukemia research
1.88
DOIOpen Access PDFOpenAlex
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