Histone deacetylase inhibition sensitizes TP53-mutated B-cell precursor acute lymphoblastic leukemia to chemotherapy
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE234091 | GEO | 2024/01/10
REPOSITORIES: GEO
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Project description:Histone deacetylase inhibition sensitizes TP53-mutated B-cell precursor acute lymphoblastic leukemia to chemotherapy
| PRJNA980094 | ENA
Project description:Background & Aims: Histone deacetylases (HDACs) are among the most common epigenetic dysregulations found in cancer, and considered as key events in tumour development and progression. Here we explored the therapeutic effects of romidepsin, a class-I HDAC inhibitor (HDACi), alone and in combination with receptor tyrosine kinase inhibitors (RTKi) in hepatocellular carcinoma (HCC). Methods: We bioinformatically evaluated class-I HDACs relevance in HCC patients through available datasets. Effects of romidepsin were assessed in HCC cell and mouse models. Molecular alterations were determined using proteomics, biochemistry, metabolic assays, immunostaining. The proteomic analysis was performed on Huh7 human HCC cell line non-treated or treated with romidepsin, cabozantinib or their combination, for 24h. Results: We report that overexpression of HDAC1 and HDAC2 occurs in HCC patients across five cohorts, and is correlated with decreased overall survival. We found that their targeting by romidepsin in HCC cell lines affects levels of several signals involved in cell cycle/survival and confers RTKi responsiveness. Mechanistically, romidepsin perturbs lipid metabolism, reduces cholesterol levels and upregulates fatty acid modulators. Furthermore, romidepsin affects the mitotic spindle machinery, leading to monopolar spindle formation, altered chromosome segregation, and cell blockage into mitosis illustrated by an accumulation of phospho-histone H3 positive HCC cells. Combined treatment of HCC cells with romidepsin plus cabozantinib (RomiCabo) switches a cytostatic effect, by romidepsin alone, into cell death by apoptosis. In vivo, RomiCabo induces regression of a subset of spontaneous preneoplastic as well as advanced lesions in the Alb-R26Met model faithfully recapitulating HCC resistance and heterogeneity. We characterize the upregulation of HR23B, a biomarker for tumour sensitivity to HDAC inhibition, and downregulation of the HCC marker AFP in RomiCabo treated Alb-R26Met tumours. Conclusions: Our findings provide the rationale of using romidepsin to exacerbate the vulnerability of HCC to RTKi for the treatment of patient subgroups.
2025-08-04 | PXD041166 | Pride
Project description:The BCL-2 inhibitor venetoclax combined with the hypomethylating agent azacitidine or with low-dose cytarabine significantly improves response rates and overall survival (OS) for newly diagnosed unfit and relapsed / refractory (R/R) acute myeloid leukemia (AML) patients. We retrospectively analyzed our experience with venetoclax combination therapy in 41 unfit AML patients (23 untreated, 18 R/R). Overall response rates were 78.3% for untreated patients and 61.1% for R/R patients. TP53 alterations were observed in 13 patients (31.7%) and were identified as an independent predictor of poor outcome (p=0.0008). We further conducted single-cell RNA sequencing in bone marrow, sampled before and after venetoclax and azacitidine treatment, of three TP53-mutated AML patients who achieved complete remission (CR) or CR with incomplete hematologic recovery. After treatment, numbers of cells expressing anti-apoptotic genes such as BCL2 and MCL1 decreased. CD4 T cells, cytotoxic CD8 T cells, and NK cells significantly increased both in number and in levels of gene expression associated with cytotoxicity post-treatment, confirming immune recovery in the tumor microenvironment. Residual AML cells expressed CD47 and CLEC12A (CLL1). These results indicate that venetoclax combination therapy of AML is promising in real-world clinical practice and suggest a role for ancillary treatment targeting antigens expressed on residual AML cells as a therapeutic strategy in TP53-mutated AML.
2025-08-30 | GSE306339 | GEO
Project description:Global gene expression analysis was performed on 8 cancer cell lines after treatment with romidepsin for 6h, or 6h treatment followed by 12 h incubation with drug free medium. The cell lines were selected based on their response spectrum to romidepsin, and included HUT78, LOXIMVI, M14, A549, MDA231, ACHN, MiaPaca2 and PC3. Differentially expressed genes (DEG) included genes involved in DNA damage repair (DDR) pathways. The Affymetrix Human Genome U133 Plus 2.0 platform was used for the gene expression profiling.
2021-04-29 | GSE133120 | GEO
Project description:Diffuse midline gliomas (DMGs) are lethal brain tumors characterized by inactivating p53 mutations and oncohistone H3.3K27M mutations that rewire the cellular response to genotoxic stress, presenting therapeutic opportunities. We used RCAS/tv-a retroviruses and Cre recombinase to inactivate p53 and induce K27M in the native H3f3a allele in a lineage- and spatially-directed manner, yielding primary mouse DMGs. Disruption of the DNA damage response kinase Ataxia-telangiectasia mutated (Atm) enhanced the efficacy of focal brain irradiation, extending mouse survival. This finding suggests that targeting ATM will enhance the efficacy of radiation therapy for p53-mutant DMG but not p53-wildtype DMG. We used spatial in situ transcriptomics and an allelic series of primary murine DMG models to identify transactivation-independent p53 activity as the key mediator of such radiosensitivity.
2023-11-04 | GSE246584 | GEO
Project description:TP53-mutated myeloid malignancies are associated with complex cytogenetics and extensive structural variants, which complicates detailed genomic analysis by conventional clinical techniques. We performed whole-genome sequencing (WGS) of 42 acute myeloid leukemia (AML)/myelodysplastic syndromes (MDS) cases with paired normal tissue to better characterize the genomic landscape of TP53-mutated AML/MDS. WGS accurately determines TP53 allele status, a key prognostic factor, resulting in the reclassification of 12% of cases from monoallelic to multihit. Although aneuploidy and chromothripsis are shared with most TP53-mutated cancers, the specific chromosome abnormalities are distinct to each cancer type, suggesting a dependence on the tissue of origin. ETV6 expression is reduced in nearly all cases of TP53-mutated AML/MDS, either through gene deletion or presumed epigenetic silencing. Within the AML cohort, mutations of NF1 are highly enriched, with deletions of 1 copy of NF1 present in 45% of cases and biallelic mutations in 17%. Telomere content is increased in TP53-mutated AMLs compared with other AML subtypes, and abnormal telomeric sequences were detected in the interstitial regions of chromosomes. These data highlight the unique features of TP53-mutated myeloid malignancies, including the high frequency of chromothripsis and structural variation, the frequent involvement of unique genes (including NF1 and ETV6) as cooperating events, and evidence for altered telomere maintenance.
| S-EPMC10425686 | biostudies-literature
Project description:Chemoresistance challenges the clinical application of most widely used platinum-based cancer chemotherapeutics which canonically function through inducing DNA damage. The DNA sensor cyclic GMP–AMP synthase (cGAS) connects genome instability to type I IFN response which confers vulnerability to platinum treatment. Here, by using a high throughput small-molecule-microarray-based screening of cGAS interacting compounds, we identified brivanib, known as an inhibitor of the vascular endothelial growth factor receptor (VEGFR), as a novel cGAS agonist. Brivanib markedly enhanced platinum-induced STING-TBK1-type I IFN response in tumor cells indispensable of cGAS. Importantly, brivanib synergizes the effect of cisplatin in restricting the growth of xenografted Lewis Lung Cancer (LLC) cells by boosting CD8+ T cell response in a cGAS-dependent manner. Mechanistically, brivanib enhances the DNA binding affinity of cGAS by directly targeting leucine 495 of cGAS. Moreover, leucine 495 of cGAS is essential for brivanib-mediated promoting effect on cisplatin-mediated type I IFN response and inhibition of tumor growth. Clinically, higher expression of cGAS in tumor renders a more favorable response to platinum-based chemotherapeutic regimens and better prognosis in lung cancer patient. Taken together, our findings discover cGAS as an unprecedented target of brivanib and provide a rationale for the combination of brivanib with platinum-based chemotherapeutics in cancer treatment.
2022-12-31 | GSE190016 | GEO
Project description:ARID1A is a subunit of SWI/SNF chromatin remodeling complexes and is mutated in many types of human cancers, especially those derived from endometrial epithelium, including ovarian and uterine clear cell carcinoma (CCC) and endometrioid carcinoma (EMCA). Loss-of-function mutations in ARID1A alter epigenetic regulation of transcription, cell-cycle checkpoint control, and DNA damage repair. We report here that mammalian cells with ARID1A deficiency harbor accumulated DNA base lesions and increased abasic (AP) sites, products of glycosylase in the first step of base excision repair (BER). ARID1A mutations also delayed recruitment kinetics of BER long-patch repair effectors. Although ARID1A-deficient tumors were not sensitive to monotherapy with DNA-methylating temozolomide (TMZ), the combination of TMZ with PARP inhibitors (PARPi) potently elicited double-strand DNA breaks, replication stress, and replication fork instability in ARID1A-deficient cells. The TMZ and PARPi combination also significantly delayed in vivo growth of ovarian tumor xenografts carrying ARID1A mutations and induced apoptosis and replication stress in xenograft tumors. Together, these findings identified a synthetic lethal strategy to enhance the response of ARID1A-mutated cancers to PARP inhibition, which warrants further experimental exploration and clinical trial validation.SignificanceThe combination of temozolomide and PARP inhibitor exploits the specific DNA damage repair status of ARID1A-inactivated ovarian cancers to suppress tumor growth.
| S-EPMC10527942 | biostudies-literature
Project description:TP53 mutations are associated with adverse outcomes and shorter response to hypomethylating agents (HMAs) in myelodysplastic syndrome (MDS). Limited data have evaluated the impact of the type, number, and patterns of TP53 mutations in response outcomes and prognosis of MDS. We evaluated the clinicopathologic characteristics, outcomes, and response to therapy of 261 patients with MDS and TP53 mutations. Median age was 68 years (range, 18-80 years). A total of 217 patients (83%) had a complex karyotype. TP53 mutations were detected at a median variant allele frequency (VAF) of 0.39 (range, 0.01-0.94). TP53 deletion was associated with lower overall response rate (ORR) (odds ratio, 0.3; P = .021), and lower TP53 VAF correlated with higher ORR to HMAs. Increase in TP53 VAF at the time of transformation was observed in 13 patients (61%), and previously undetectable mutations were observed in 15 patients (65%). TP53 VAF was associated with worse prognosis (hazard ratio, 1.02 per 1% VAF increase; 95% confidence interval, 1.01-1.03; P < .001). Integration of TP53 VAF and karyotypic complexity identified prognostic subgroups within TP53-mutant MDS. We developed a multivariable model for overall survival that included the revised International Prognostic Scoring System (IPSS-R) categories and TP53 VAF. Total score for each patient was calculated as follows: VAF TP53 + 13 × IPSS-R blast score + 16 × IPSS-R cytogenetic score + 28 × IPSS-R hemoglobin score + 46 × IPSS-R platelet score. Use of this model identified 4 prognostic subgroups with median survival times of not reached, 42.2, 21.9, and 9.2 months. These data suggest that outcomes of patients with TP53-mutated MDS are heterogeneous and that transformation may be driven not only by TP53 but also by other factors.
| S-EPMC7013259 | biostudies-literature
Project description:Upregulation of the Wilms' Tumor 1 (WT1) gene is common in acute myeloid leukemia (AML) and is associated with poor prognosis, including disease relapse, decreased overall survival (OS), and chemotherapy resistance. WT1 produces 12 primary transcripts through different translation initiation sites and alternative splicing, but the specific transcripts and mechanisms responsible for chemoresistance are unknown. We found that overexpression of short WT1 transcripts lacking exon 5 with and without the KTS motif (sWT1+/- and sWT1-/-) led to reduced cell growth. However, only sWT1+/- resulted in decreased CD71 expression, G1 arrest, and cytarabine resistance. Primary AML patient cells with low CD71 expression exhibit relative resistance to cytarabine, suggesting that CD71 may serve as a potential biomarker for cytarabine therapy. RNAseq differential gene expression analysis identified two transcription factors, HOXA3 and GATA2, that are specifically upregulated in sWT1+/- cells. Overexpression of either HOXA3 or GATA2 reproduced the effects of sWT1+/-, including decreased cell growth, G1 arrest, reduced CD71 expression, and cytarabine resistance. Furthermore, sWT1+/-, HOXA3, and GATA2 regulate cell growth and cytarabine sensitivity in a context-dependent manner, likely dependent on HOXA3 expression. HOXA3 expression is significantly correlated with chemotherapy response, OS, and ELN subtypes in NPM1-negative leukemia specimens. Overexpression of HOXA3 leads to drug resistance against a broad spectrum of chemotherapeutic agents. Our results suggest that WT1 modulates drug sensitivity in an isoform-specific manner by promoting HOXA3 expression. Both HOXA3 mRNA and CD71 cell surface expression could serve as potential biomarkers for predicting responses to cytarabine-based treatment in AML.
2024-07-31 | GSE239734 | GEO