Chidamide inhibits double expressor lymphoma through repressing Myc expression and activity
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ABSTRACT:
PROVIDER: PRJNA725123 | ENA |
REPOSITORIES: ENA
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Project description:Double-expressor lymphoma (DEL), defined by MYC and BCL-2 overexpression without corresponding chromosome translocations, is often associated with poor outcomes for standard treatment (R-CHOP). Recently, inhibitors of histone deacetylases have shown great effect in T cell lymphomas. However, its effects on B cell lymphomas are mild. Here, our clinical retrospective analysis showed that HDAC inhibitor chidamide combined with R-CHOP (CR-CHOP) can dramatically increase the complete remission rate of patients with DEL. And the sensitivity of B cell lymphoma cell lines to chidamide is negatively correlated to Myc level. From Western blots and transcriptomics analysis, we found that chidamide treatment could reduce Myc protein level and downregulate the transcription levels of corresponding Myc downstream targets. Thus our results indicate that HDAC inhibitor chidamde holds great potential for treating DEL, which likely functions through inhibiting the Myc pathway.
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Project description:We report that Chidamide shows significant anti- proliferation and more specifically anti-NOTCH effects in both cell lines and primary cells of T-ALL patients. By analyzing the expression profile characterizing the response of the cell lines to Chidamide treatment, we further confirmed that the antitumor effect of Chidamide was due to the inhibition of HDAC and the anti-NOTCH1 effect.
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Project description:Chidamide inhibits the NOTCH1-MYC signaling axis in T-cell acute lymphoblastic leukemia
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Project description:Rituximab/chemotherapy relapsed and refractory B cell lymphoma patients have a poor overall prognosis, and it is urgent to develop novel drugs for improving the therapies of these patients. A new oral histone deacetylase inhibitor, chidamide shows anti-tumor activity by activating the pro-apoptosis pathway in some other hematological malignancies, suggesting its potential application to the relapsed and refractory B cell lymphoma. In this study, we examined the therapeutic effects of chidamide on the cell and mouse models of the rituximab/chemotherapy resistant B cell lymphoma, as well as the primary B cell lymphoma cells. In Raji-4RH and RL-4RH cells, the rituximab/chemotherapy resistant B cell lymphoma cell lines (RRCL), chidamide treatment induced growth inhibition and G0/G1 cell cycle arrest, which were associated with E2F1/2 inactivation and CDK2 degradation. The primary B cell lymphoma cells from Rituximab/chemotherapy relapsed and refractory patients were also very sensitive to chidamide treatment. Interestingly, chidamide triggered the cell death via the autophagy pathway instead of the activation of apoptosis in Raji-4RH and RL-4RH cells, likely due to the lack of the pro-apoptotic proteins in these resistant cells. In the RNA-seq and chromatin immunoprecipitation (ChIP) analysis, we identified BTG1 and FOXO1 as the direct target genes of chidamide, which control the autophagy and cell cycle respectively in RRCL treated with chidamide. Moreover, the combination of chidamide with the chemotherapy drug Cisplatin sensitized the RRCL to growth inhibition in a synergistic manner. Chidamide-Cisplatin combination significantly reduced the tumor burden of a mouse lymphoma model established with engraftment of RRCL. Taken together, our studies provides a theoretic and mechanistic basis for further evaluation of the chidamide-based clinical trial for rituximab/chemotherapy relapsed and refractory B cell lymphoma patients.
2021-10-06 | GSE137359 | GEO
Project description:Natural Killer/T-cell lymphoma (NKTL) is a rare type of aggressive and heterogeneous non-Hodgkin's lymphoma (NHL) with poor prognosis and limited therapeutic options. Here, we demonstrate that chidamide, a novel histone deacetylase (HDAC) inhibitor, is effective in treating relapsed/refractory NKTL patients, achieving an overall response rate of 39.3%, with 17.9% complete response rate. However, the clinical response to chidamide remains variable as more than half of the patients exhibit primary resistance, limiting its utility in NKTL treatment. To unravel the resistance mechanisms of chidamide, we performed integrative transcriptomic and chromatin profiling of sensitive and resistant NKTL cells. Our results revealed that aberrant JAK-STAT signaling remodels the chromatin and confers resistance to chidamide. Subsequently, inhibition of JAK-STAT activity could overcome resistance to chidamide by reprogramming the chromatin from a resistant to sensitive state, leading to synergistic anti-tumor effect. More importantly, our clinical data demonstrated that combinatorial therapy with chidamide and JAK inhibitor ruxolitinib is effective against chidamide-resistant NKTL. In addition, we identified TNFRSF8 (CD30), a downstream target of JAK-STAT pathway, as a potential biomarker that could predict NKTL sensitivity to chidamide. Collectively, our study suggests that chidamide, in combination with JAK-STAT inhibitors, can be a novel targeted therapy in the standard of care for NKTL.
2023-03-02 | GSE152185 | GEO
Project description:To explore the potential mechanism of chidamide in BM-MSC-mediated adipogenesis, we have employed mRNA microarray expression profiling platform to identify significant differential genes associated with adipogenic differentiation and chidamide management.
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Project description:To provide a new treatment strategy for patients with acute myeloid leukemia (AML), we investigated the therapeutic effect and mechanism of chidamide combined with cytarabine in AML.
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Project description:Frequent inactivating mutations of histone acetyltransferase CREBBP is a characteristic feature of diffuse large B-cell lymphoma (DLBCL), highlighting the attractiveness of targeting the CREBBP deficiency as a therapeutic strategy. In this study, we demonstrate that chidamide, a novel histone deacetylase (HDAC) inhibitor, is effective in treating a subgroup of relapsed/refractory DLBCL patients, achieving an overall response rate (ORR) of 25.0% and a complete response (CR) rate of 15.0%. However, the clinical response to chidamide remains poor as most patients exhibit resistance, hampering the clinical utility of the drug. Functional studies in both in vitro and in vivo models showed that CREBBP loss of function is correlated with chidamide sensitivity, which is associated with modulating cell cycle machinery. A combinatorial drug screening of 130 kinase inhibitors targeting cell cycle regulators identified AURKA inhibitors, which inhibited G2/M transition during cell cycling, as top candidates that synergistically enhanced antitumor effects of chidamide in CREBBP-proficient DLBCL cells. Our study demonstrated that CREBBP inactivation can serve as a potential biomarker to predict chidamide sensitivity, while a combination of AURKA inhibitor and chidamide provides a novel therapeutic strategy for the treatment of relapsed/refractory DLBCL.
2024-02-24 | GSE167383 | GEO
Project description:Homoharringtonine (HHT), a previously known protein synthesis inhibitor, has anti-myeloid leukemia effect and potentiates the therapeutic efficacy of anthracycline/cytarabine induction regimens for acute myeloid leukemia (AML) with favorable and intermediate prognosis, especially in t(8;21) subtype. Here we provide evidence to show that HHT inhibits the activity of leukemia-initiating cells (Lin-/Sca-1-/c-kit+, LICs) in t(8;21) murine leukemia model and exerts down-regulating effect on MYC pathway genes in human t(8;21) leukemia cells (Kasumi-1). By using biochemistry approach, NF-κB-repressing factor (NKRF) was discovered to be bound directly by HHT via the second double-strand RNA binding motif (DSRM2) domain, which is the nuclear localization signal (NLS) of NKRF. A series of deletion and mutagenesis experiments mapped HHT direct binding site to K479 and C480 amino acids in the DSRM2 domain. HHT treatment shifts NKRF from nucleus (including nucleoli) to cytoplasm through occupying the DSRM2 domain, strengthens p65-NKRF interaction, and interferes with the p65-p50 complex formation, thereby attenuating the transactivation activity of p65 on MYC gene. Moreover, HHT significantly decreases the expression of KIT, a frequently mutated and/or highly expressed gene in t(8;21) AML, in consistence with MYC downregulation. Our work has thus identified a mechanism different to, but in concert with, the classical mode of action of HHT and justifies its further clinical exploration in the treatment of AML.
2018-12-31 | GSE121175 | GEO