Histone deacetylase inhibitor targets CD123/CD47-positive cells and reverse chemoresistance phenotype in acute myeloid leukemia

Yan, Bowen; Chen, Qinwei; Shimada, Kōji; Tang, Ming; Li, Haoli; Gurumurthy, Aishwarya; Khoury, Joseph D.; Xu, Bing; Huang, Suming; Qiu, Yi

doi:10.1038/s41375-018-0279-6

Cited by 47 publications

(37 citation statements)

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“…Hence, combining HDACis with other chemotherapeutic agents is considered to be an effective way to enhance tumor drug sensitivity by improving the cellular efficacy and toxicity of HDACis to tumor cells [116][117][118][119][120][121][122][123][124][125] (Table 3 and Table 4). To date, the different mechanisms of HDACis combined with chemotherapeutic agents such as topoisomerase inhibitors, platinumbased chemotherapeutics, proteasome inhibitors, tyrosine kinase pathway inhibitors and epigenetic modifiers for advanced or drug-resistant hematological malignancies include (1) acetylating histones and inducing p21-CDK-mediated cell cycle arrest; (2) inducing apoptosis by regulating the expression of pro-and antiapoptotic genes through the intrinsic or extrinsic pathway; (3) inducing DNA damage and oxidative stress; (4) activating BTK (in CLL) or inhibiting ERK (in MM) and AKT (in CML) signaling pathways; and (5) regulating the expression of drug resistance-related molecules, such as downregulating BCR-ABL and upregulating Bim in hematological malignancies and downregulating CD44 in multiple myeloma (MM), NF-κB in ALL, γ-catenin in CML, and BRCA1, CHK1 and RAD51 in AML [126][127][128][129][130][131][132][133][134][135][136][137][138][139][140][141][142][143][144][145]. Specific combination strategies and their corresponding mechanisms are summarized in Table 3 [146][147][148]…”

Section: The Application Of Hdacis In Malignant Hematopoiesismentioning

confidence: 99%

Role of HDACs in normal and malignant hematopoiesis

2020

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Normal hematopoiesis requires the accurate orchestration of lineage-specific patterns of gene expression at each stage of development, and epigenetic regulators play a vital role. Disordered epigenetic regulation has emerged as a key mechanism contributing to hematological malignancies. Histone deacetylases (HDACs) are a series of key transcriptional cofactors that regulate gene expression by deacetylation of lysine residues on histone and nonhistone proteins. In normal hematopoiesis, HDACs are widely involved in the development of various lineages. Their functions involve stemness maintenance, lineage commitment determination, cell differentiation and proliferation, etc. Deregulation of HDACs by abnormal expression or activity and oncogenic HDAC-containing transcriptional complexes are involved in hematological malignancies. Currently, HDAC family members are attractive targets for drug design, and a variety of HDAC-based combination strategies have been developed for the treatment of hematological malignancies. Drug resistance and limited therapeutic efficacy are key issues that hinder the clinical applications of HDAC inhibitors (HDACis). In this review, we summarize the current knowledge of how HDACs and HDAC-containing complexes function in normal hematopoiesis and highlight the etiology of HDACs in hematological malignancies. Moreover, the implication and drug resistance of HDACis are also discussed. This review presents an overview of the physiology and pathology of HDACs in the blood system.

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Section: The Application Of Hdacis In Malignant Hematopoiesismentioning

confidence: 99%

Role of HDACs in normal and malignant hematopoiesis

2020

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“…HDAC plays an essential role in leukemic development and progression, and its inhibition increased the sensitivity to cytotoxic agents in AML cells [1]. Combination of HDAC inhibitor with chemotherapeutic drug is a potentially effective approach to improve antileukemia effect and eradicate LSC in AML through disruption of multiple signaling pathways and accumulation of DNA damage [53][54][55][56]. We showed previously that combined inhibition of HDAC and proteasome degradation had a synergistic antileukemia activity in chemoresistant AML cells [1].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of EZH2 by chidamide exerts antileukemia activity and increases chemosensitivity through Smo/Gli-1 pathway in acute myeloid leukemia

Jiang

Cheng

et al. 2020

Preprint

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Background: Dysregulation of epigenetics plays important roles in leukemogenesis and progression of acute myeloid leukemia (AML). Histone acetyltransferases (HATs) and histone deacetylases (HDACs) reciprocally regulate acetylation and deacetylation of nuclear histone, aberrant activation of HDAC results in uncontrolled proliferation and differentiated blockage, HDAC inhibitors have been investigated as therapeutic drugs for treatment of AML. Methods: Cell growth was assessed by CCK-8 assay, apoptosis was determined by flow cytometry in AML cell lines, CD45+ and CD34+CD38- cells from patient’s samples after stained with Annexin V-fluorescein isothiocyanate (FITC)/Propidium Iodide (PI). EZH2 expression was silenced by short hairpin RNA (shRNA). The pathway changes were detected by western blot. The effect of chidamide or EZH2 shRNA in combination with adriamycin was studies in vivo in nude mice model bearing leukemia.Results: In this study, we investigated the antileukemia activities of HDAC inhibitor chidamide and its combinatorial effect with cytotoxic agent in AML. We demonstrated in vitro and in vivo that chidamide suppressed expression of EZH2, exerted potential antileukemia activity and increased the sensitivity AML cells and AML stem/progenitor cells to chemotherapeutic drug through Smo/Gli-1 pathway. In addition to decrease the expression of H3K27me3 and DNMT3A, inhibition of EZH2 either pharmacologicall by chidamide or genetically by shEZH2 decreased the activity of Smo/Gli-1 pathway, and increased chemotherapeutic sensitivity in AML cells. Conclusions: Inhibition of EZH2 by chidamide has antileukemia activity and increases chemosensitivity, it provides a potential strategy to improve chemotherapeutic effect in AML.

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“…Relapse was a major challenge for the long‐term outcome of AML patients and may be caused by the persistence of LSCs. LSCs have been reported to be quiescent, well protected within the bone marrow niche, resistant to chemotherapy, and responsible for recurrent disease . Some reports have demonstrated that the frequency of LSCs in patients with AML might be prognostic .…”

Section: Discussionmentioning

confidence: 99%

“…LSCs have been reported to be quiescent, well protected within the bone marrow niche, resistant to chemotherapy, and responsible for recurrent disease. 30 Some reports have demonstrated that the frequency of LSCs in patients with AML might be prognostic. 31,32 Evidence for the identification of LSCs involves a demonstration of the capacity to successfully reconstitute leukemia by engrafting cells into immunodeficient mice.…”

Section: Cd34+aldh+-h/mrd-h Status Independently Predicts Relapsementioning

confidence: 99%

High aldehyde dehydrogenase activity at diagnosis predicts relapse in patients with t(8;21) acute myeloid leukemia

et al. 2019

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Acute myeloid leukemia (AML) with t(8;21) is a heterogeneous disease. Although the detection of minimal residual disease (MRD), which is indicated by RUNX1‐RUNX1T1 transcript levels, plays a key role in directing treatment, risk stratification needs to be improved, and other markers need to be assessed. A total of 66 t(8;21) AML patients were tested for aldehyde dehydrogenase (ALDH) activity by flow cytometry at diagnosis, and 52 patients were followed up for a median of 20 (1‐34) months. The median percentage of CD34+ALDH+, CD34+CD38‐ALDH+, and CD34+CD38+ALDH+ cells among nucleated cells were 0.028%, 0.012%, and 0.0070%, respectively. The CD34+ALDH+‐H, CD34+CD38‐ALDH+‐H, and CD34+CD38+ALDH+‐H statuses (the percentage of cells that were higher than the individual cutoffs) were all significantly associated with a lower 2‐year relapse‐free survival (RFS) rate in both the whole cohort and adult patients (P = .015, .016, and .049; P = .014, .018, and .032). Patients with < 3‐log reduction in the RUNX1‐RUNX1T1 transcript level after the second consolidation therapy (defined as MRD‐H) had a significantly lower 2‐year RFS rate than patients with ≥ 3‐log reduction (MRD‐L) (P = .017). The CD34+ALDH+ status at diagnosis was then combined with the MRD status. CD34+ALDH+‐L/MRD‐H patients had similar 2‐year RFS rates to both CD34+ALDH+‐L/MRD‐L and CD34+ALDH+‐H/MRD‐L patients (P = .50 and 1.0); and CD34+ALDH+‐H/MRD‐H patients had significantly lower 2‐year RFS rate compared with CD34+ALDH+‐L and/or MRD‐L patients (P < .0001). Multivariate analysis showed that CD34+ALDH+‐H/MRD‐H was an independent adverse prognostic factor for relapse. In conclusion, ALDH status at diagnosis may improve MRD‐based risk stratification in t(8;21) AML, and concurrent high levels of CD34+ALDH+ at diagnosis and MRD predict relapse.

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Histone deacetylase inhibitor targets CD123/CD47-positive cells and reverse chemoresistance phenotype in acute myeloid leukemia

Cited by 47 publications

References 50 publications

Role of HDACs in normal and malignant hematopoiesis

Role of HDACs in normal and malignant hematopoiesis

Inhibition of EZH2 by chidamide exerts antileukemia activity and increases chemosensitivity through Smo/Gli-1 pathway in acute myeloid leukemia

High aldehyde dehydrogenase activity at diagnosis predicts relapse in patients with t(8;21) acute myeloid leukemia

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