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The MLLT3 YEATS domain is a dual reader of histone marks (H3K9/18/27ac/cr) and ncRNA (7SK), linking epigenetic and RNA signaling to regulate hematopoiesis [RNA-Seq]

ABSTRACT: Herein we describe our findings that the YEATS domain of MLLT3 is not only a reader of histone acetylation and crotonylation but also binds to ncRNA.

ORGANISM(S): Mus musculus

PROVIDER: GSE303246 | GEO | 2026/05/20

REPOSITORIES: GEO

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The MLLT3 YEATS domain is a dual reader of histone marks (H3K9/18/27ac/cr) and ncRNA (7SK), linking epigenetic and RNA signaling to regulate hematopoiesis [PRO-Seq]

Project description:Herein we describe our findings that the YEATS domain of MLLT3 is not only a reader of histone acetylation and crotonylation but also binds to ncRNA.

2026-05-20 | GSE303247 | GEO

The MLLT3 YEATS domain is a dual reader of histone marks (H3K9/18/27ac/cr) and ncRNA (7SK), linking epigenetic and RNA signaling to regulate hematopoiesis

Project description:This SuperSeries is composed of the SubSeries listed below.

2026-05-20 | GSE303306 | GEO

Transcriptomic profiling of MLL-ENL and delta YEATS mutant

Project description:To investigate the contribution of ENL YEATS domain and downstream sequences in MLL-ENL leukemogenesis program, we generated MLL-ENL and MLL-ENL ∆YEATS (ENL aa372-559) cell lines by retrovirally introducing these constructs into lineage negative hematopoietic stem and progenitor cells (HSPCs).

2023-02-27 | GSE211523 | GEO

RNA-seq of MLLT3-L and MLLT3-S overexpressing cultured HSPC, compared to non-overexpressing and uncultured FL-HSPC

Project description:MLLT3 preserves the FL-HSPC gene expression signature in culture.

2024-05-31 | GSE252221 | GEO

A chemical-genetic interaction between PAF1 and ENL/AF9 YEATS inhibition

Project description:Transcriptional regulatory proteins are frequent drivers of oncogenesis and common targets for drug discovery. The transcriptional co-activator, ENL, which binds to chromatin through an acetyllysine reader YEATS domain, is preferentially required for the survival and pathogenesis of acute leukemia. Small molecules that inhibit the ENL YEATS domain show anti-leukemia effects in preclinical models, which is thought to be caused by the downregulation of pro-leukemic ENL target genes. However, the transcriptional effects of ENL YEATS domain inhibitors have not been studied in models of intrinsic or acquired resistance and, therefore, the connection between proximal transcriptional effects and downstream anti-proliferative effects is poorly understood. To address this, we identified models of intrinsic and acquired resistance and used them to study the effects of ENL YEATS domain inhibitors. We first discovered that ENL YEATS domain inhibition produces similar transcriptional responses in naive models of sensitive and resistant leukemia. We then performed a CRISPR/Cas9-based genetic modifier screen and identified in-frame deletions of the essential transcriptional regulator, PAF1, that confer resistance to ENL YEATS domain inhibitors. Using isogenic models of PAF1-mediated resistance, we again found that the downregulation of ENL target genes is shared in both sensitive and resistant leukemia. Altogether, these data support the conclusion that the suppression of ENL target genes is not sufficient to explain the anti-leukemia effects of ENL antagonists.

2025-12-02 | GSE304765 | GEO

The Taf14 YEATS domain is a reader of histone crotonylation.

Project description: Not available

| S-EPMC4871749 | biostudies-literature

FLT3-N676K drives acute myeloid leukemia in a xenograft model of KMT2A-MLLT3 leukemogenesis

Project description:Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements. Herein, we show that co-expression of FLT3-N676K and KMT2A-MLLT3 in human CD34+ cord blood cells primarily cause acute myeloid leukemia (AML) and rarely acute lymphoblastic leukemia (ALL) in immunodeficient mice. By contrast, expression of KMT2A-MLLT3 alone cause ALL, double-positive leukemia (DPL, expressing both CD33 and CD19), or bilineal leukemia (BLL, comprised of distinct myeloid and lymphoid leukemia cells), and rarely AML. Further, AML could only be serially propagated with maintained immunophenotype in secondary recipients when cells co-expressed KMT2A-MLLT3 and FLT3-N676K. Consistent with the idea that activated signaling would allow myeloid cells to engraft and maintain their self-renewal capacity, in a secondary recipient, a de novo KRAS-G13D was identified in myeloid cells previously expressing only KMT2A-MLLT3. Gene expression profiling revealed that KMT2A-MLLT3 DPL had a highly similar gene expression profile to ALL, with both expressing key lymphoid transcription factors and ALL cell surface markers, in line with the DPL cells being ALL cells with aberrant expression of CD33. Taken together, our results highlight the need for constitutive active signaling mutations for driving myeloid leukemia in a human xenograft model of KMT2A-R acute leukemia.

2019-04-05 | GSE127492 | GEO

Analysis of chromatin accessibility in uncultured fetal liver hematopoietic stem-progenitor cells and upon MLLT3 overexpression [ATACseq]

Project description:MLLT3 binds to open gene TSS

2019-03-06 | GSE111480 | GEO

RNA-seq of MLLT3-overexpressing cultued HSPC, compared to non-overexpressing and uncutured FL-HSPC [RNAseq_MLLT3_OE]

Project description:MLLT3 preserves the FL-HSPC gene expression signature in culture

2019-03-06 | GSE111483 | GEO

Chemical inhibition of ENL/AF9 YEATS domains in acute leukemia [RNA-Seq]

Project description:Transcriptional co-regulators, which mediate chromatin-dependent transcriptional signaling, represent tractable targets to modulate tumorigenic gene expression programs with small molecules. Genetic loss-of-function studies have recently implicated the transcriptional co-activator, ENL, as a selective requirement for the survival of acute leukemia – particularly those driven by multiple lineage leukemia (MLL)-fusion oncogenes. The YEATS domain of ENL, which binds to chromatin by interacting with acyl-lysine side chains, is critical for its pathogenic function in acute leukemiaand highlighted an essential role for its chromatin reader YEATS domain. Motivated by these recent discoveries, we executed a screen of nearly 300,000 small molecules to identify chromatin-competitiveand identified an amido-imidazopyridine inhibitors of the ENL YEATS domain (IC50 = 7 µM). Leveraging a SuFEx-based high-throughput approach to Optimizing an amido-imidazopyridine scaffold with highly parallelized, SuFEx-based medicinal chemistry optimization, we discovered SR-0813 (IC50 = 25 nM), a potent and selective ENL/AF9 YEATS domain inhibitor that exclusively inhibits the growth of ENL-dependent leukemia cell lines. Armed with this tool and a first-in-class ENL PROTAC, SR-1114, we detailed the response of AML cells to pharmacological ENL disruption for the first time. Most notably, displacement of In AML cells, SR-0813 evicts ENL from chromatin, by SR-0813 preferentially suppresseselicited a strikingly selective suppression of ENL target genes, including HOXA9/10, MYB, MYC and a number of other leukemia proto-oncogenes. Our study reproduces a number of key observations previously made by CRISPR/Cas9 loss of function and dTAG-mediated degradation, and therefore, both reinforces ENL as an emerging leukemia target and validates SR-0813 as a high-quality chemical probe.

2020-12-04 | GSE162592 | GEO

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