Ding Yali, He Bing, Bogush Daniel, Schramm Joseph, Singh Chingakham, Dovat Katarina, Randazzo Julia, Tukaramrao Diwakar, Hengst Jeremy, Annageldiyev Charyguly, Kudva Avinash, Desai Dhimant, Sharma Arati, Spiegelman Vladimir S, Huang Suming, Viet Chi T, Dorsam Glenn, Saulnier Scholler Giselle, Broach James, Yue Feng, Dovat Sinisa
Department of Pediatrics, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Department of Medicine, Pennsylvania State University College of Medicine, Hershey, PA, USA.
Leukemia. 2025 Jun 24. doi: 10.1038/s41375-025-02651-1.
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.
IKZF1基因编码IKAROS，它是一种DNA结合蛋白，在T细胞急性淋巴细胞白血病（T-ALL）中作为肿瘤抑制因子发挥作用。IKAROS可通过募集组蛋白去乙酰化酶1（HDAC1）和染色质重塑来充当转录抑制因子，然而，IKAROS在T-ALL中通过异染色质发挥其肿瘤抑制功能的机制在很大程度上尚不清楚。我们使用功能丧失和IKZF1重新表达方法，结合原发性人类T-ALL以及正常人类和小鼠胸腺细胞，研究了人类和小鼠的T-ALL，以确定IKAROS和HDAC1在T-ALL中对兼性异染色质的全局调控和转录抑制中的作用。结果确定了IKAROS和HDAC1在T-ALL中的新功能：IKAROS和HDAC1对于EZH2组蛋白甲基转移酶活性和兼性异染色质的形成都是必不可少的；IKAROS对HDAC1的募集对于H3K27me3组蛋白修饰的建立和活性增强子的抑制至关重要；IKAROS-HDAC1复合物促进T-ALL中H3K27me3大组织染色质赖氨酸（K）结构域（LOCKs）和广泛基因抑制结构域（BGRDs）的形成和扩展。我们的结果确立了IKAROS和HDAC1在EZH2激活、兼性异染色质景观的全局调控以及调节癌基因表达的活性增强子沉默中的核心作用。
