Histone Acetyltransferase Complex Research Articles (Page 1)

Chromatin remodeling activity of EP400 safeguards chromosomal stability by preventing CENP-A mislocalization.

Plant histone acetyltransferase complexes: Conserved and plant-specific characteristics.

INHIBITOR OF GROWTH (ING) proteins are chromatin readers that bind trimethylated histone H3 lysine (K) 4 (H3K4me3) marks and associate with either histone acetyltransferase or deacetylase complexes to activate or repress gene transcription, respectively. In plants, there are two types of ING proteins, namely ING1 and ING2. Here, we report that Arabidopsis thaliana ING2 associates with multiple subunits of the histone H4 acetyltransferase complex NuA4, controls genome-wide levels of histone H4 acetylation (H4ac), and regulates different developmental processes, including the initiation of flowering. Our data indicate that ING2 biological functions are largely independent of ING1 activity. We find that ING2 is recruited to the chromatin of key floral integrators, such as FT and SOC1, and is required for their timely activation by modulating histone H4ac levels at these loci. Our observations reveal a genetic interaction between ING2 and genes encoding relevant proteins for H3K4me3 or H2A.Z deposition, suggesting that ING2 might represent a hub for potential crosstalk between histone H4ac and these histone modifications/variants.

Protein arginine methyltransferase 5 (PRMT5) has pleiotropic functions in human cells but also participates in orchestrating DNA double strand break (DSB) repair. It methylates the TIP60 histone acetyltransferase complex to facilitate recruitment to the DSB and chromatin remodeling. PRMT5 mutations affect DSB repair by homologous recombination and increase chromosomal instability. In this report we characterized genetic interactions between PRMT5 mutations and mutations in other components of DSB repair pathway. We used data deposited on the Catalogue of Somatic Mutations in Cancers (COSMIC). We found that PRMT5 makes negative genetic interactions with TIP60 and member of the 9-1-1 complex (RAD9, RAD1, HUS1) which is required for checkpoint activation. A comprehensive analysis of all cancer data deposited on COSMIC reveals very few samples with mutations in both PRMT5 and TIP60 or components of the 9-1-1 complex in samples where mutations in other DNA damage repair genes occur (e.g., MRN, checkpoint genes, etc). This suggests that when more factors of the DNA damage repair machinery are destabilized, the functions of TIP60 and 9-1-1 appear to become essential. Protein 3-D structure analysis shows that mutations affect protein-protein interactions that may destabilize 9-1-1 or TIP60 complex formation. These data highlight interesting interactions between the various genetic pathways governing DSB repair. It also reveals potential therapeutic targets. For example, inhibition of the 9-1-1 complex in a PRMT5 mutant may selectively kill the cell. Given that PRMT5 small molecule inhibitors are being developed or already deployed, these findings should inform potential applications of these drugs.

Jade1 and the HBO1 histone acetyltransferase complex are spatial-selective cofactors of the pluripotency transcription factor Oct4

Oct4 is a master regulator of pluripotency. Potential Oct4 interactors have been cataloged but the manner and significance of these interactions are incompletely defined. Oct4 is capable of binding to DNA in multiple configurations, however the relationship between these configurations and cofactor recruitment (and hence transcription output) are unknown. Here, we show that Oct4 interacts with common and unique proteins when bound to DNA in different configurations. A unique protein is Jade1, a component of HBO histone acetyltransferase complexes. Jade1 preferentially associates with Oct4 when bound to M ore palindromic O ctamer- R elated E lement (MORE) DNA sequences that bind Oct4 dimers. Surprisingly, we find that the Oct4 N-terminal activation domain, rather than facilitating Jade1 binding, serves as an autoinhibitory domain that dampens the interaction. ChIP-seq using HBO1, the enzymatic component of the complex, identifies a preference for binding adjacent to Oct4 at MORE sites. Using purified recombinant proteins and nucleosome complexes, we show that the HBO1 complex acetylates histone H3K9 within nucleosomes more efficiently when Oct4 is co-bound to a MORE. An Oct4 mutant with superior MORE binding characteristics also shows superior ability to catalyze H3K9 acetylation. Jade1 knockdown reduces H3K9Ac at regions where Oct4 binds a MORE but not a simple octamer. Cryo-electron microscopy reveals that Oct4 bound to a MORE near the nucleosome entry/exit site partially unwinds DNA from nucleosome core particles, and identifies additional mass associated with the HBO1 complex. These results identify a novel mechanism of transcriptional regulation by Oct4.

In mammals, chromosome-wide regulatory mechanisms ensure a balance of X-linked gene dosage between males (XY) and females (XX). In female cells, expression of genes from one of the two X chromosomes is curtailed, with selective accumulation of Xist-RNA, Xist-associated proteins, specific histone modifications (for example, H3K27me3) and Barr body formation observed throughout interphase. Here we show, using chromosome flow-sorting, that during mitosis, Xist-associated proteins dissociate from inactive X (Xi) chromosomes, while high levels of H3K27me3 and increased compaction of the Xi relative to active X (Xa), are retained. Proteomic comparison of mitotic Xi and Xa revealed that components of Hbo1 and Msl/Mof histone acetyltransferase complexes are significantly enriched on Xa as compared to Xi and autosomes. By contrast, inhibitors of histone acetylation co-enrich with Xi. Furthermore, inhibition of Hbo1 or deletion of Msl/Mof components functionally abolishes mitotic differences in H3K27me3 marking and chromosome compaction. These data uncover critical roles for acetylation pathways in preserving X chromosome properties during mitosis.

To adapt to seasonal changes, many animals, particularly insects, enter a dormancy-like condition known as diapause, which is primarily accomplished by sensing photoperiodic signals. The circadian clock, which is driven by positive regulators Clock (CLK) and Cycle (CYC), and negative regulators Period and Timeless, is thought to mediate this response. However, it remains unclear whether diapause induction involves a canonical rhythmic mechanism or occurs independently of their traditional roles in timekeeping. Using the ladybug Harmonia axyridis as a model for short-day-induced winter diapause, we demonstrate that knockdown of Clk and cyc, but not per or tim, disrupted entry into reproductive diapause. This finding demonstrated that Clk-cyc regulates diapause independently of per and tim. We further show that the DNA methyltransferase 1-associated protein 1 (DMAP1)-mediated Nucleosome Acetyltransferase of H4 (NuA4)/TIP60 histone acetyltransferase complex impinges on diapause regulation by acting simultaneously as a downstream effector and a physical interactor of CLK-CYC. Application of the juvenile hormone (JH) receptor agonist methoprene effectively rescued the diapause phenotypes caused by Clk, cyc, and dmap1 knockdowns, highlighting the central role of the CLK-CYC-NuA4/TIP60 complex in JH production. Additionally, using a corpora allata (CA)-specific driver in Drosophila melanogaster, we demonstrate that this complex functions locally in the CA to mediate JH biosynthesis. Collectively, our findings identify a previously unrecognized pathway by which circadian clock proteins interact with an epigenetic regulator to specifically govern JH biosynthesis in a critical endocrine tissue, thereby regulating diapause entry independently of canonical circadian clock mechanisms.

TRRAP encodes a multidomain pseudokinase involved in histone acetyltransferase complexes. TRRAP pathogenic variants were linked to neurodevelopmental disorders, intellectual disability, congenital anomalies, and hearing loss. We report on three unrelated patients with TRRAP missense variants. Patient #1, a girl with severe intellectual disability, autism features, and preaxial polydactyly, displays the c.5575C>T, p.(Arg1859Cys) variant. Patient #2, a boy with developmental delay and facial anomalies, harbors the c.5647G>A, p.(Gly1883Arg) variant. Patient #3, a girl with developmental delay, epilepsy, and renal artery stenosis, carries the c.8572C>T, p.(Arg2858Trp) variant. These new cases broaden the TRRAP phenotypic spectrum, updating genotype-phenotype correlations. Osteoclast differentiation in Patient #1 and TRRAP expression in osteoclasts and osteoblasts were analyzed, leading to the assumption of a role of TRRAP in bone remodeling and in the observed skeletal anomalies.

Sustained drought tolerance in plants relies on transcriptional memory through successive stress cycles, yet the chromatin-based mechanisms underlying this memory remain unclear. Previously, we revealed that PtrMYB161 overexpression in Populus trichocarpa results in phenotypes characteristic of drought tolerance. Here, we confirm that such transgenesis instills an epigenetic path to gene transregulation for drought tolerance. PtrMYB161 binds directly to the MYB-core motif in the promoter of PtrNAC120, a drought response/tolerance gene, to recruit the histone acetyltransferase (HAT) dimer GENERAL CONTROL NON-DEREPRESSIBLE5-1-ALTERATION/DEFICIENCY IN ACTIVATION2b-3 (PtrGCN5-1-PtrADA2b-3), forming the ternary protein complex (PtrMYB161-PtrGCN5-1-PtrADA2b-3). This ternary system enables enhanced acetylation of nucleosome histone 3 lysine-9, -14, and -27 (H3K9, H3K14, and H3K27) for enriched RNA Pol II occupancy in the PtrNAC120 promoter to elevate its expression for drought tolerance. Unlike PtrAREB1-2, an important drought-inducible transcription factor that can also mediate PtrNAC120 transactivation for tolerance, PtrMYB161 expression remains unaffected by drought. However, under drought conditions, induced PtrAREB1-2 could form HAT ternary complex, PtrAREB1-2-PtrGCN5-1-PtrADA2b-3, and bind to PtrAREB1-binding sites (ABREs) in the PtrNAC120 promoter for PtrNAC120's enhanced H3K acetylation, RNA Pol II occupancy, and transactivation for drought tolerance. PtrMYB161-PtrGCN5-1-PtrADA2b-3-mediated PtrNAC120 transactivation was induced following severe, prolonged drought stress (below 40% relative soil water content) and PtrAREB1-2-induced PtrNAC120 transactivation. Further loss- and gain-of-function transgenesis experiments in whole plants and stem differentiating xylem protoplasts suggest that, under stress, the PtrAREB1-2 regulatory system activates an ancillary regulation mediated by PtrMYB161. Our findings propose coordinated epigenetic regulations mediated by HAT complexes to jointly sustain drought tolerance in Populus.

KAT6A and KAT7 associate with NUP98 FOs to drive leukemogenesis. Inhibition of their HAT activity is an effective therapeutic strategy in NUP98-r leukemias, including those resistant to menin inhibition. Moreover, combined KAT6A/7 and menin inhibition is synergistic, supporting clinical translation to improve outcomes for NUP98 FO-driven leukemias.

Triple-negative breast cancer (TNBC) is a particularly aggressive and frequently recurring form of breast cancer, where chemotherapy is the primary treatment approach. Unfortunately, the development of resistance to chemotherapy poses a considerable challenge, restricting the already limited therapeutic alternatives for recurrent cases. Here, we generated two Taxol-resistant TNBC cell lines with a dose-escalation method to mimic chemotherapy resistance in vitro. These cells exhibited reduced growth rates, altered morphology and evasion of apoptosis. Transcriptome analysis uncovered elevated ABCB1 expression and multidrug-resistant phenotype in these resistant cells. To comprehensively investigate the key epigenetic regulators of Taxol resistance, we conducted chromatin-focused genetic and chemical screens and pinpointed Bromodomain and PHD Finger Containing 1 (BRPF1) as a novel regulator of Taxol resistance. Knockout of BRPF1, the reader protein in the MOZ–MORF histone acetyltransferase complex, but not the other complex members, sensitized resistant cells to Taxol. In addition, BRPF1 inhibitors, PFI-4 and OF-1, in combination with Taxol significantly reduced cell viability. Transcriptome analysis upon BRPF1 loss or inhibition revealed a negative impact on ribosome biogenesis-related gene sets, resulting in a global decrease in protein translation in Taxol-resistant cells. CUT&RUN-qPCR analysis demonstrated that BRPF1 directly binds to the ABCB1 promoter, enhancing its expression toward inducing a multidrug-resistant phenotype. Conversely, knockout or inhibition of BRPF1 leads to decreased ABCB1 expression. Our findings uncover a comprehensive molecular framework, highlighting the pivotal role of epigenetic reader protein BRPF1 in Taxol resistance and providing potential avenues for therapeutic intervention in TNBC.

Members of the INhibitor of Growth protein family (ING1-5) function as epigenetic regulators by targeting different histone acetyltransferase (HAT) and histone deacetylase (HDAC) complexes to the H3K4Me3 mark of active transcription. The INGs recognize H3K4Me3 by specific interaction with their well-conserved plant homeodomains, and affinity can be increased by interactions between DNA and disordered regions within the ING proteins. They are classified as type II tumor suppressors since they are downregulated in numerous cancer types and knockout of ING family members results in tumorigenesis. ING4 targets the HBO1 HAT complex, which is known to affect acetylation of the H4 core nucleosomal histone, to affect local chromatin structure and knockout results in deficient innate immunity. Reports indicating roles in cell cycle regulation, tumor suppression, and apoptosis suggest that ING4 may be a promising target for cancer treatment by targeting pathways of innate immunity. Given the relatedness between ING4 and the closely related ING5 proteins, we have developed and characterized two mouse monoclonal antibodies to specifically recognize human and mouse ING4, but not ING5, to more accurately characterize ING4 levels by western, immunofluorescence and immunohistochemical assays. Using them, we show that ING4 differentially partitions between the nucleus and cytoplasm in different tissues and localizes largely to the cytoplasm of cells having a secretory role in different tissue types.

Hepatocellular carcinoma (HCC) is the predominant form of primary liver cancer and a major contributor to cancer-related mortality globally. Central to its pathogenesis is the dysregulation of lipid metabolism in hepatocytes, leading to abnormal lipid accumulation. Our bioinformatics analysis has identified the histone acetyltransferase complex subunit VPS72 as being associated with HCC, yet the precise molecular mechanisms through which VPS72 contributes to hepatocarcinogenesis remain poorly understood. Our analysis of extensive HCC patient cohorts identifies a significant proportion with VPS72 copy number gains, which are strongly linked to adverse prognostic outcomes. By integrating RNA-Seq, ChIP-Seq, ATAC-seq, and experimental validation, we show that VPS72 overexpression activates mTORC1 signaling, subsequently promoting lipid synthesis and driving HCC progression. We further uncover that VPS72 modulates the epigenetic landscape by enhancing DNA methylation at the ATF3 promoter, resulting in ATF3 repression and subsequent activation of mTORC1. This study elucidates a novel regulatory axis that links dysregulated lipid metabolism with HCC progression, highlighting potential epigenetic and metabolic targets for therapeutic intervention.

Abstract Background: Sarcomas are heterogenous neoplasms originating in mesenchymal tissues such as muscles, fat, nerves, blood vessels, etc. Our lab has previously shown that the Hippo signaling pathway is perturbed in sarcomas, and TAZ/YAP, the end effectors of the Hippo pathway, are key oncoproteins driving sarcomagenesis. Epithelioid hemangioendothelioma (EHE), a vascular sarcoma, is predominantly driven by the fusion protein TAZ-CAMTA1, which promotes cancer hallmarks and alters gene expression patterns by interacting with YEATS2 and ZZZ3, which are key scaffolds of the Ada2A-Containing (ATAC) histone acetyltransferase (HAT) complex. YEATS2 is a histone reader and binds H3K27-acetyl, and ZZZ3 binds the histone H3 tail, and both YEATS2 and ZZZ3 are necessary for the proper assembly of the ATAC complex, which subsequently acetylates H3K9, a key histone modification necessary for gene transcription. Previously, we have utilized RNA-sequencing data from The Cancer Genome Atlas and shown that high YEATS2/ZZZ3 RNA levels correlate with a worse overall survival in multiple histological subtypes of sarcomas. Methods: We performed western blot analysis to measure YEAST2/ZZZ3 protein levels in human sarcoma cell lines. We utilized siRNA/shRNA to knockdown YEATS2/ZZZ3 and measured H3K9-acetyl protein levels via western blot analysis. Apart from genetic inhibition, we utilized HAT-inhibitors and performed several in vitro cancer hallmarks, such as 3D soft agar assays and poly-HEMA assays to measure anchorage-independent growth and MTT-based assays to measure 2D proliferation. We also performed a cell-line-derived xenograft experiment where we injected immunocompromised NSG mice with SW872 cells expressing TAZ-CAMTA1 with or without stable knockdown of YEATS2. Results: We observed that YEATS2/ZZZ3 protein levels are upregulated in multiple human sarcoma cells. We also observed that genetic and pharmacological inhibition of the ATAC complex in both fusion protein-positive (SW872 cells expressing TAZ-CAMTA1) and -negative (SKLMS; leiomyosarcoma and HT1080; fibrosarcoma) sarcoma cells decreases H3K9-acetyl protein levels. In the xenograft experiment, knockdown of YEATS2 significantly decreased tumor initiation and progression in NSG mice as compared to non-targeting cells. In SKLMS, YEATS2 knockdown significantly reduced 2D proliferation and colony formation on soft agar. Conclusion: Our data show that in both fusion protein-positive and -negative sarcomas, the ATAC complex is a key histone acetyltransferase for H3K9. We show that the ATAC complex promotes tumorigenesis in vivo in a xenograft mouse model. In the leiomyosarcoma cell line SKLMS, the ATAC complex promotes 2D proliferation and anchorage-independent growth in vitro, which are key cancer hallmarks. Overall, our studies show that the ATAC complex is a potential therapeutic target in multiple sarcomas, such as EHE and leiomyosarcoma. Citation Format: Souradip Sinha, Krishnendu Ghosh, Ali Khan, Yuliia Drebot, Gillian DeWane, Nicholas Scalora, Samuel Yu, Keith Garcia, Munir R. Tanas. The ATAC histone acetyltransferase complex is a key oncogenic driver in sarcomas [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4097.

Abstract Acute myeloid leukemia (AML) is a heterogeneous malignancy characterized by genetic and epigenetic dysregulation, including aberrant activity of chromatin modifiers. The complex interactions among these modifiers and regulators in AML pathogenesis remain poorly understood, posing significant challenges to developing effective combination therapies. To address this, we used Perturb-seq, a CRISPR-based single-cell transcriptomics approach, to profile 16 key genes from the Menin-MLL, Polycomb, and histone acetyltransferase (HAT) complexes in the MOLM-13 AML cell line. We developed a machine learning framework called Composer, which predicts the combinatorial effects of perturbations by analyzing their impact on the transcriptome. We identified cooperative regulation of oncogenic pathways by Menin-MLL and KAT6A, while PRC1 components, such as PCGF1, were found to antagonize DOT1L activity. These predictions were validated using bulk RNA-seq and experiments combining perturbations through small molecule inhibitors and gene knockouts, demonstrating that dual inhibition of Menin-MLL and KAT6A, or DOT1L and KAT6A, significantly reduced AML cell viability. This study underscores the power of combining AI with single-cell Perturb-seq to provide novel insight into the epigenetic landscape of AML and identify promising therapeutic targets to overcome treatment resistance. Citation Format: Changde Cheng, Rui Lu, Sajesan Aryal, Doug A. Welsch. Uncovering synergistic and antagonistic interactions in epigenetic therapeutics using perturb-seq [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 219.

MSL1, a scaffold protein of the MSL histone acetyltransferase complex, is crucial for its structural integrity and enzymatic activity. While MSL1 is highly expressed in various tumors, its role in tumor progression and cell death remains unclear. Here, we provide evidence of a negative regulatory relationship between MSL1 and KCTD12 through biochemical assays and knockdown/overexpression studies. Notably, in colon cancer cells, the ferroptosis inducer Erastin significantly suppressed MSL1 expression, leading to KCTD12 upregulation. Moreover, MSL1 promotes Erastin-induced ferroptosis in HCT116 and SW480 cells via the KCTD12-SLC7A11 axis. Consistently, Erastin-induced changes in ROS, GSH, and MDA levels were regulated by this axis, highlighting its role in ferroptosis. These findings offer potential therapeutic targets and a theoretical foundation for colon cancer treatment.

Wax mixtures comprising very long-chain fatty acids and their derivatives represent the major cuticular components and protect plant tissues from environmental stresses. Uncovering the regulatory mechanisms underlying wax biosynthesis is essential for the genetic improvement of the agronomically important crop bread wheat (Triticum aestivum L.). Herein, partially redundant ECERIFERUM 3 (TaCER3) proteins were characterized as essential components of wheat wax biosynthetic machinery. Furthermore, we demonstrated that the wheat enoyl-CoA reductase promoter-binding MYB transcription factor 1 (TaEPBM1)could directly target TaCER3 genes and recruit components of the SAGA histone acetyltransferase complex to mediate histone acetylation, thereby stimulating TaCER3 transcription and potentiating wax biosynthesis. Wheat RNA processing machineries, including the RNA exosome, SUPERKILLER complex, cap-binding complex (CBC) components, TaSERRATE, and its partners, as well as elongator subunits, affected the accumulation of TaCER3 transcripts and controlled wax biosynthesis. Silencing of wheat CBC components, TaSERRATE, and elongator subunits resulted in the accumulation of TaCER3 transcripts and increased wax biosynthesis. Importantly, the activation of wheat wax biosynthesis in the absence of RNA processing factors was suppressed by silencing TaCER3 expression. These findings suggest that the SAGA histone acetyltransferase complex functions in concert with the RNA processing machinery to regulate wheat wax biosynthesis, probably via affecting TaCER3 genes.

BRD1 encodes a protein containing a bromodomain, which is an essential component of histone acetyltransferase (HAT) complexes. These complexes play a crucial role in the regulation of gene transcription and the modification of chromatin structures. The aberrant expression of BRD1 is frequently observed across a range of cancer types, including hepatocellular carcinomas (HCC). However, the precise mechanisms through which BRD1 contributes to tumorigenesis, especially in HCC, remain unclear. In our investigation, we have uncovered a novel role for BRD1 as an oncogene implicated the regulation of lipid metabolism in HCC progression. Specifically, the deficiency of BRD1 impedes the proliferation and metastasis of HCC cells reducing the accumulation of lipid droplets and cholesterol levels. This effect is mediated through the SREBF1-induced downregulation of SCD1 expression in HCC cells. Mechanistically, the ablation of BRD1 disrupts acetylation level of H3K9, culminating in the subsequent trimethylation of H3K9 (H3K9me3). Notably, the H3K14ac partially colocalizes with H3K9me3 and its methyltransferase SETDB1 to from a double labeling of both H3K14ac and H3K9me3 at the SREBF1 promoter. This double labeling contributes to the creation of a repressive environment, ultimately leading to the downregulation of SREBF1 gene expression in HCC. Furthermore, the combinatorial use of a BRD1 inhibitor and simvastatin augments antitumor efficacy in vivo. Collectively, our findings underscore BRD1 as a critical regulator of SREBF1-associated lipid metabolism and a participant in HCC progression through a distinct epigenetic regulatory mechanism. These discoveries further suggest a promising epigenetic therapeutic approach for the treatment of HCC.

FMS-like tyrosine kinase-3 (FLT3), a class 3 receptor tyrosine kinase, can be activated by mutations of internal tandem duplication (FLT3-ITD) or point mutations in the tyrosine kinase domain (FLT3-TKD), leading to constitutive activation of downstream signaling cascades, including the JAK/STAT5, PI3K/AKT/mTOR and RAS/MAPK pathways, which promote the progression of leukemic cells. Despite the initial promise of FLT3 inhibitors, the discouraging outcomes in the treatment of FLT3-ITD-positive acute myeloid leukemia (AML) promote the pursuit of more potent and enduring therapeutic approaches. The histone acetyltransferase complex comprising the E1A binding protein P300 and its paralog CREB-binding protein (p300/CBP) is a promising therapeutic target, but the development of effective p300/CBP inhibitors faces challenges due to inherent resistance and low efficacy, often exacerbated by the absence of reliable clinical biomarkers for patient stratification. In this study we investigated the role of p300/CBP in FLT3-ITD AML and evaluated the therapeutic potential of targeting p300/CBP alone or in combination with FLT3 inhibitors. We showed that high expression of p300 was significantly associated with poor prognosis in AML patients and positively correlated with FLT3 expression. We unveiled that the p300/CBP inhibitors A485 or CCS1477 dose-dependently downregulated FLT3 transcription via abrogation of histone acetylation in FLT3-ITD AML cells; in contrast, the FLT3 inhibitor quizartinib reduced the level of H3K27Ac. Concurrent inhibition of p300/CBP and FLT3 enhanced the suppression of FLT3 signaling and H3K27 acetylation, concomitantly reducing the phosphorylation of STAT5, AKT, ERK and the expression of c-Myc, thereby leading to synergistic antileukemic effects both in vitro and in vivo. Moreover, we found that p300/CBP-associated transcripts were highly expressed in quizartinib-resistant AML cells with FLT3-TKD mutation. Targeting p300/CBP with A485 or CCS1477 retained the efficacy of quizartinib, suggesting marked synergy when combined with p300/CBP inhibitors in quizartinib-resistant AML models, as well as primary FLT3-ITD+ AML samples. These results demonstrate a potential therapeutic strategy of combining p300/CBP and FLT3 inhibitors to treat FLT3-ITD and FLT3-TKD AML.