Dataset Information

RUNX1 expression is regulated by a super-enhancer and is a therapeutic target in adult T-cell leukemia/lymphoma

ABSTRACT: Super-enhancers (SEs)—genomic enhancer regions with dense accumulation of mediator complexes—play an important role in regulating tumor-specific gene expression and are potential therapeutic targets for neoplastic diseases. Bromodomain-containing protein 4 (BRD4) is a component of the protein complexes that bind to the SE region. JQ1, one of the known BRD4 inhibitors, exerts antitumor effects by suppressing SE-mediated regulation of gene expression. Adult T-cell leukemia/lymphoma (ATL) is highly resistant to available treatments, and its prognosis is extremely poor. As JQ1 has potential as a therapeutic agent for various malignancies, we investigated the anti-ATL effects of JQ1. JQ1 induced apoptosis and inhibited ATL cell proliferation. JQ1 suppressed the expression of RUNX1 through the disruption of SE-mediated gene regulation, indicating that RUNX1 could be a novel therapeutic target molecule. AI-10-104 and Ro5-3335 are RUNX1 inhibitors developed for hematologic malignancies such as acute myeloid leukemia (AML) and lymphoblastic leukemia (ALs). We demonstrated that these two agents reduced cell proliferation in ATL cell lines and patient samples at effective concentrations in ALs with RUNX1 mutations. Simultaneously, AI-10-104 suppressed MYC proto-oncogene (c-MYC) expression. RUNX1 is a potential therapeutic target for ATL that promotes c-MYC expression. For the first time, we showed that RUNX1 expression is regulated via SEs in ATL, a hematologic malignancy of peripheral mature T cells. This study indicates that RUNX1 may be a novel therapeutic target for ATL.

ORGANISM(S): Homo sapiens

PROVIDER: GSE253457 | GEO | 2025/01/13

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Following the discovery of BRD4 as a non-oncogene addiction target in acute myeloid leukemia (AML), BET inhibitors are being explored as promising therapeutic avenue in numerous cancers. While clinical trials have reported single-agent activity in advanced hematologic malignancies, mechanisms determining the response to BET inhibition remain poorly understood. To identify factors involved in primary and acquired BET resistance in leukemia, we performed a chromatin-focused shRNAmir screen in a sensitive MLL/AF9; NrasG12D‑driven AML model, and investigated dynamic transcriptional profiles in sensitive and resistant murine and human leukemias. Our screen reveals that suppression of the PRC2 complex, contrary to effects in other contexts, promotes BET resistance in AML. PRC2 suppression does not directly affect the regulation of Brd4-dependent transcripts, but facilitates the remodeling of regulatory pathways that restore the transcription of key targets such as Myc. Similarly, while BET inhibition triggers acute MYC repression in human leukemias regardless of their sensitivity, resistant leukemias are uniformly characterized by their ability to rapidly restore MYC transcription. This process involves the activation and recruitment of WNT signaling components, which compensate for the loss of BRD4 and drive resistance in various cancer models. Dynamic ChIP- and STARR-seq enhancer profiles reveal that BET-resistant states are characterized by remodeled regulatory landscapes, involving the activation of a focal MYC enhancer that recruits WNT machinery in response to BET inhibition. Together, our results identify and validate WNT signaling as a driver and candidate biomarker of primary and acquired BET resistance in leukemia, and implicate the rewiring of transcriptional programs as an important mechanism promoting resistance to BET inhibitors and, potentially, other chromatin-targeted therapies. RNA-Seq of DMSO- or JQ1-treated cancer cell lines; ChIP-seq for H3K36me3 and H3K27me3 in a leukemia cell line treated either with DMSO or JQ1, ChIP-seq for H3K27ac in resistant and sensitive mouse and human leukemia. Functional enhancer mapping (STARR-seq) in K-562 treated either with DMSO or JQ1.

Dataset Information

RUNX1 expression is regulated by a super-enhancer and is a therapeutic target in adult T-cell leukemia/lymphoma

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets