Clinical and Translational Medicine
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2020
·Vol. 10
·期 4
·e154
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IF 7.919
Xiaoxuan Yu,Hui Li,Po Hu,Yingjie Qing,Xiangyuan Wang,Mengyuan Zhu,Hongzheng Wang,Zhanyu Wang,Jingyan Xu,Qinglong Guo,Hui Hui
Background Although targeting histone deacetylases (HDACs) may be an effective strategy for core binding factor-acute myeloid leukemia (CBF-AML) harboring t(8;21) or inv(16), HDAC inhibitors are reported to be limited by drug-resistant characteristic. Our purpose is to evaluate the anti-leukemia effects of Baicalein on CBF-AML and clarify its underlying mechanism. Methods Enzyme activity assay was used to measure the activity inhibition of HDACs. Rhodamine123 and RT-qPCR were employed to evaluate the distribution of drugs and the change of ATP-binding cassette (ABC) transporter genes. CCK8, Annexin V/PI, and FACS staining certified the effects of Baicalein on cell growth, apoptosis, and differentiation. Duolink and IP assay assessed the interaction between HDAC-1 and ubiquitin, HSP90 and AML1-ETO, and Ac-p53 and CBFβ-MYH11. AML cell lines and primary AML cells-bearing NOD/SCID mice models were used to evaluate the anti-leukemic efficiency and potential mechanism of Baicalein in vivo. Results Baicalein showed HDAC-1/8 inhibition to trigger growth suppression and differentiation induction of AML cell lines and primary AML cells. Although the inhibitory action on HDAC-1 was mild, Baicalein could induce the degradation of HDAC-1 via ubiquitin proteasome pathway, thereby upregulating the acetylation of Histone H3 without promoting ABC transporter genes expression. Meanwhile, Baicalein increased the acetylation of HSP90 and lessened its connection to AML1/ETO, consequently leading to degradation of AML1-ETO in t(8;21)q(22;22) AML cells. In inv(16) AML cells, Baicalein possessed the capacity of apoptosis induction accompanied with p53-mediated apoptosis genes expression. Moreover, CBFβ-MYH11-bound p53 acetylation was restored via HDAC-8 inhibition induced by Baicalein contributing the diminishing of survival of CD34 + inv(16) AML cells. Conclusions These findings improved the understanding of the epigenetic regulation of Baicalein, and warrant therapeutic potential of Baicalein for CBF-AML.
研究领域:
肿瘤学
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分子生物学
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药理学
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表观遗传学
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Scientific Reports
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2016
·Vol. 6
·期 1
·1-12
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IF 5.228
Ma Qiang,Wang Chuan,Li Xiaojin,Guo Hua,Meng Jie,Liu Jian,Xu Haiyan
Realgar (As 4 S 4 ) has been demonstrated to be effective for the treatment of acute myeloid leukemia (AML); it has the advantages of no drug resistance and oral administration. Nevertheless, its poor solubility has been an obstacle to its bioavailability, requiring high-dose administration over a long period. We investigated whether crushing realgar crystals to the nanoscale and encapsulating the particles in a water-soluble polymer in one step using hot-melt extrusion would increase the bioavailability of As 4 S 4 . Raw As 4 S 4 (r-As 4 S 4 ) and water-soluble polymer were processed via co-rotating twin screw extrusion. The resulting product (e-As 4 S 4 ) was characterized by SEM, XRD, and DLS. The cytotoxicity and therapeutic effects of e-As 4 S 4 were evaluated in vivo and in vitro . The results show that e-As 4 S 4 dissolved rapidly in water, forming a stable colloid solution. The average size of e-As 4 S 4 particles was 680 nm, which was reduced by more than 40-fold compared with that of r-As 4 S 4 . The bioavailability of e-As 4 S 4 was up to 12.6-fold higher than that of r-As 4 S 4 , and it inhibited the proliferation of HL-60 cells much more effectively than did r-As 4 S 4 , inducing apoptosis and significantly reducing the infiltration of HL-60 cells into the bone marrow, spleen, and liver. This in turn prolonged the survival of AML mice.
研究领域:
药理学
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肿瘤学
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材料科学
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治疗学
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EXPERIMENTAL CELL RESEARCH
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2020
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IF 3.383
Fan Zhao,Luchen Sun,Nanfei Yang,Wei Zheng,Pingping Shen,Yahong Huang,Yan Lu
Extensive literature has demonstrated that acute myeloid leukaemia (AML) cells show enhanced mitochondrial biogenesis and increased reliance on oxidative phosphorylation (OXPHOS) compared with normal hematopoietic progenitors, and one hallmark of AML leukaemia blasts is myeloid differentiation blockade. However, relatively few reports have linked these processes. Recent studies have indicated that therapies that overcome differentiation arrest represent an effective treatment strategy. Here, we identified that the disruption of the mitochondrial mass and energy metabolism promotes leukaemia cellular myeloid differentiation. In this study, we showed that acute monocytic leukaemia (AML-M5) cells package mitochondria in microvesicles (MVs) when MVs shed from membranes. Additionally, during myeloid differentiation, we report for the first time that differentiated leukaemia cells release more MVs than undifferentiated leukaemia cells. Targeting the formation of MVs using a specific inhibitor (Y-27632) restrained myeloid differentiation, suggesting that the increased release level of MVs plays an important role in regulating myeloid differentiation. Furthermore, the intracellular mitochondria and ATP levels were decreased after leukaemia cells overcame the differentiation blockade. Moreover, rotenone , which is used to inhibit the respiratory chain and ATP production, had a strong effect on myeloid differentiation in monocytic leukaemia cells. Collectively, these studies uncovered the relationship between mitochondrial function and myeloid differentiation and may provide more insight into the diagnosis and treatment of AML.
研究领域:
血液学
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肿瘤学
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细胞生物学
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分子生物学
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Marine Drugs
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2025
·Vol. 23
·期 7
·289
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IF 5.4
Shijie Bi,Yating Cao,Shiyuan Fang,Yanyan Chu,Zixuan Zhang,Meng Li,Rilei Yu,Jinbo Yang,Yu Tang,Peiju Qiu
The internal tandem duplication mutation of FMS-like tyrosine kinase 3 (FLT3-ITD) is associated with high recurrence and mortality rates in acute myeloid leukemia (AML), making it a critical target for anti-AML therapies. Plinabulin is a diketopiperazines derivative that exhibits extensive anti-cancer potency by targeting β-tubulin. We designed and synthesized a novel FLT3 inhibitor, namely5-3, based on the structure of plinabulin and evaluated its effect on FLT3-ITD mutant AML cells. The results indicated that5-3potently and selectively inhibits the growth of mutant FLT3-expressingleukemia cells, and had no effect on FLT3 wide-type cancer cells, suggesting the antiproliferative activity of5-3depends highly on FLT3-ITD expression. Mechanically,5-3significantly suppressed the phosphorylation of FLT3 signaling pathway, including STAT5, Erk and Akt. Moreover, the efficiency of compound5-3is not associated with Plinabulin’s typical target, β-tubulin. In conclusion, the study identified diketopiperazine derivative as a novel FLT3-ITD selective inhibitor. These results demonstrated that5-3might be a drug candidate for the treatment of FLT3-ITD-positive AML.
研究领域:
肿瘤学
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药物化学
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分子生物学
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血液学
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药理学
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2023
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IF 6.1
Wan Wang,Hang Shang,Jinzhe Li,Yue Ma,Cong Xu,Jiage Ma,Juncai Hou,Zhanmei Jiang
Polyphenols have received attention as dietary supplements for the relief of alcoholic liver disease (ALD) due to various bioactivities. Ethanol-induced rat small intestinal epithelial cell 6 (IEC-6) and alpha mouse liver 12 (AML-12) cell models were pretreated with four dietary polyphenols with different structures to explore their effects on cytotoxicity and potential protective mechanisms. The results showed that polyphenols had potential functions to inhibit ethanol-induced AML-12 and IEC-6 cell damage and oxidative stress, and restore ethanol-induced IEC-6 permeability and tight junction gene expression. Especially, dihydromyricetin (DMY) had the best protective effect on ethanol-induced cytotoxicity, followed by apigenin (API). Western blot results showed that DMY and API had the best ability to inhibit CYP2E1 and Keap1, and promote nuclear translocation of Nrf2, which might be the potential mechanism by which DMY and API attenuate ethanol-induced cytotoxicity. Moreover, the molecular docking results predicted that DMY and API could bind more tightly to the amino acid residues of CYP2E1 and Keap1, which might be one of the inhibitory modes of dietary polyphenols on CYP2E1 and Keap1. This study provided a rationale for the subsequent protective effect of dietary polyphenols on alcohol-induced liver injury in animal models and provided new clues on bioactive components for ALD-protection based on the gut-liver axis.
研究领域:
药理学
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毒理学
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细胞生物学
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分子生物学
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Cell Death & Disease
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2026
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IF 12.2
Zeng Yuqing,He Chao,Chen Hongbo,Cheng Fang
Upregulation of autophagy in acute myeloid leukemia (AML) cells contributes to the development of resistance to cytarabine (AraC). LAPTM5 is mainly expressed in hematopoietic and immune cells, and has been associated with the progression of multiple cancers; however, its role in AML drug resistance remains uncharacterized. Here, we reanalyzed publicly available single-cell RNA sequencing (scRNA-seq) data from AML patients and found distinct gene expression profiles between AraC-resistant AML cells and untreated controls. Differentially expressed genes were significantly enriched in lysosome-related pathways, with LAPTM5 being highly expressed in drug-resistant cells, suggesting that it may be a key mediator of AraC resistance in AML. Mechanistically, AraC-resistant cells exhibited enhanced autophagic flux supported by LAPTM5-mediated upregulation of LAMP1 and LAMP2. Conversely, LAPTM5 knockdown impaired autophagolysosome formation by disrupting lysosomal biogenesis, thereby sensitizing resistant cells to AraC. These findings indicate that targeting LAPTM5 could enhance AraC sensitivity in AML by modulating autophagy. In vivo experiments further confirmed that the depletion of LAPTM5 inhibited tumor growth and synergistically suppressed AML progression with AraC. Collectively, our study identifies LAPTM5 as a critical regulator of AraC resistance via autophagy modulation, highlighting its potential as a therapeutic target for AML. In AML, AraC treatment induces LAPTM5 upregulation, which promotes LAMP1/2 transcription and lysosomal biogenesis. This facilitates autophagolysosome formation and enhances autophagic flux to reduce AraC-induced apoptosis, resulting in drug resistance. Targeting LAPTM5 represents a promising strategy to overcome this autophagy-mediated resistance.
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Cancer Medicine
·
2025
·Vol. 14
·期 9
·e70872
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IF 3.1
Haitao Xu,Dangui Chen,Jia Lu,Long Zhong,Lihong Wang,Jian Ge
Background Acute myeloid leukemia (AML) represents a highly aggressive hematological malignancy characterized by a poor prognosis and a pressing demand for innovative diagnostic and prognostic biomarkers. Recent studies have indicated that ADP-ribosylation factor 6 (ARF6) is overexpressed across various cancer types; however, its specific role and implications in AML have yet to be thoroughly investigated. Methods To elucidate the clinical relevance and functional mechanisms of ARF6 in AML, we conducted an integrated analysis utilizing RNA sequencing data from The Cancer Genome Atlas (TCGA) alongside clinical samples and AML cell lines. The diagnostic potential of ARF6 was assessed through receiver operating characteristic curve analysis, and logistic regression was employed to identify factors correlating with elevated ARF6 expression. Functional assays were performed to elucidate the effects of ARF6 modulation on apoptosis, cell cycle progression, and AML cell proliferation, while mechanistic investigations focused on the PI3K/AKT/mTOR signaling pathway, particularly in the context of pharmacological PI3K inhibition. Results Our findings revealed a significant upregulation of ARF6 in AML compared to normal controls, with diagnostic efficacy indicated by an AUC of 0.793. Logistic regression analysis identified older age (> 60 years) and a higher white blood cell count (> 20 × 10 9 /L) as significant predictors of high ARF6 expression. Moreover, elevated ARF6 levels were independently associated with shorter overall survival (HR = 1.634, p = 0.045). Notably, ARF6 knockdown induced apoptosis and G0/G1 cell cycle arrest, whereas its overexpression yielded contrary effects. In addition, ARF6 activated the PI3K/AKT/mTOR pathway, which was abrogated by pharmacological PI3K inhibition. Conclusion Collectively, our findings establish ARF6 as a valuable diagnostic and prognostic marker in AML, driving disease progression through the activation of the PI3K/AKT/mTOR pathway. These insights not only enhance our understanding of AML pathology but also underscore the potential of targeting ARF6 for therapeutic intervention in AML treatment paradigms. Future research should aim at evaluating the therapeutic implications of targeting ARF6 in combination with existing treatment modalities.
研究领域:
血液学
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肿瘤学
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分子生物学
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CELL PROLIFERATION
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2026
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IF 7.6
Wanling Huang,Bo Deng,Nini Guo,Yiyi Ding,Zhangjingwen Xu,Yiwen Lu,Yue Ma,Qian Ren,Nan Wang,Pengyu Huang,Xiaotong Ma
Acute myeloid leukaemia (AML) urgently requires more reliable in vitro platforms for drug evaluation, as existing models often fail to maintain the phenotypic, metabolic, and pharmacologic features of primary leukaemic cells. To address this limitation, we developed a rapidly assembled, screening-compatible three-dimensional (3D) bioprinting platform. It encapsulates patient-derived bone marrow mononuclear cells within a gelatin-hyaluronic acid hydrogel, whose mechanical properties are tuned to match those of native bone marrow. Within this controlled 3D microenvironment, primary AML cells better maintain an in vivo-like state, showing enhanced viability, sustained proliferative capacity, preservation of stem-like subpopulations, and drug responses that more closely mirror clinical behaviour. Transcriptomic profiling further revealed robust activation of MYC target programs and mTORC1 signalling, accompanied by elevated oxidative phosphorylation and glycolytic activity, indicative of the highly proliferative and metabolically active state exhibited by AML cells in vivo. These findings demonstrate that our patient-specific, 3D bioprinted system provides a high-fidelity model. This model faithfully recapitulates AML physiology and metabolic features while capturing inter-patient variability. Consequently, it offers a more reliable and predictive platform for preclinical drug assessment.
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Science Advances
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2026
·Vol. 12
·期 24
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IF 13.9
Bo Deng,Yue Ma,Wanling Huang,Xiguang Xian,Yiyi Ding,Yifan Lu,Yaxuan Yang,Wenwen Guo,Lina Mao,Xiaoli Wang,Erlie Jiang,Xiaotong Ma,Pengyu Huang
The liver is central to drug metabolism and a critical site of disease progression, making vascularized in vitro liver models essential for disease modeling, drug discovery, and mechanistic research. However, recapitulating dynamic in vivo drug responses while maintaining clinical relevance remains a major challenge for bioartificial liver systems. In acute myeloid leukemia (AML), patients frequently develop leukemic liver infiltration and chemotherapy-induced hepatotoxicity, both of which compromise therapeutic efficacy and prognosis. Human-relevant experimental models that dynamically simulate these processes are urgently needed. Here, we developed a dynamic perfusable human vascularized liver module (DPHV-LM), constructed from in vitro–expanded primary human hepatocytes within a perfusable scaffold. Perfusion of AML patient–derived cells reproduced leukemic infiltration of liver tissue. Using the DPHV-LM for drug screening and validating findings in AML mouse models, we identified ammonium glycyrrhizinate (AMGZ) as an agent that reduces cytarabine-induced hepatotoxicity and suppresses leukemic infiltration without impairing antileukemic efficacy. The hepatoprotective trends observed in the DPHV-LM were qualitatively concordant with findings from an independent retrospective clinical cohort. Collectively, these results demonstrate the transplantational potential of this platform for modeling leukemic liver pathology and for the development of hepatoprotective therapeutic strategies.
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CELLULAR ONCOLOGY
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2026
·Vol. 49
·期 2
·55
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IF 5.6
Xin Qi,Zhang Henan,Zhao Zheng,Xu Gang,Zhang Jihong
Purpose This study aims to investigate the role of AGAP2 in acute myeloid leukemia (AML), particularly its involvement in lipid metabolic reprogramming and AML progression, and to explore the underlying regulatory mechanisms. Methods AGAP2 expression was analyzed in CD34⁺ cells from AML patients stratified by cytogenetic risk. Functional assays, including knockdown and overexpression of AGAP2, were performed in KG-1 and HL-60 AML cell lines to assess effects on proliferation, apoptosis, differentiation, and lipid metabolism. mRNA sequencing and KEGG pathway analysis were used to identify relevant signaling pathways. Lipid accumulation was evaluated via Filipin III staining. The AMPK pathway activator GSK621 was applied to examine lipid deposition. In vivo tumor growth and survival were studied in a mouse model, and bone marrow infiltration of CD45⁺ cells was analyzed. The transcriptional regulation of AGAP2 by NR2F2 was assessed through promoter binding and functional rescue experiments. Results AGAP2 was highly expressed in CD34⁺ cells from AML patients, with higher levels in the poor-risk group compared to favorable- and intermediate-risk groups. Knockdown of AGAP2 induced apoptosis and differentiation, while its overexpression promoted cell proliferation. KEGG analysis indicated enrichment of differentially expressed genes in the AMPK pathway. AGAP2 was found to inhibit AMPK/ACC pathway activation. Overexpression of AGAP2 increased lipid deposition whereas GSK621 treatment reversed it. In vivo, AGAP2 knockdown suppressed tumor growth, improved survival, and reduced CD45⁺ cell infiltration in bone marrow. Furthermore, NR2F2 bound to the AGAP2 promoter and suppressed its transcription. NR2F2 overexpression reduced lipid accumulation, an effect reversed by AGAP2 overexpression. Conclusion AGAP2 promotes lipid deposition and AML progression by inhibiting the AMPKα/ACC pathway. NR2F2 acts as a transcriptional repressor of AGAP2, thereby attenuating AML development. These findings reveal a novel NR2F2/AGAP2/AMPK/ACC regulatory axis in AML, highlighting potential therapeutic targets for lipid metabolism-based interventions in leukemia. Graphical
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JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
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2026
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IF 5.3
Xiaotian Yang,Shudan Yang,Guoqiang Lin,Shutong Chen,Huiran Jiang,Yuting Wang,Yanming Zhang,Xingxia Zhang
Aberrant activation of YAP-TEAD4 drives tumorigenesis, progression, and chemoresistance. Disrupting their interaction serves as an alternative anticancer strategy, with peptides better adapting to the large, flat interaction interface. In this study, the peptides 1–4 were screened from the peptide database via pharmacophore modelling, molecular docking, and interaction analysis. Subsequently, affinity experiments showed that among the peptides 1–4, peptide-4 possessed the lowest Kd values (Kd = 5.08 ± 0.42 nM) measured by MST and exhibited the binding affinity for TEAD4. MD simulations further demonstrated that peptide-4 stably bound to the TEAD4. MTT assays showed that peptide-4 suppressed AML-193 cell viability with an IC50 of 0.65 ± 0.04 μM. RT-qPCR assays demonstrated that Peptide-4 significantly downregulated the mRNA expression levels of CTGF and CYR61. In conclusion, the data demonstrated that the peptide-4 may serve as a promising candidate to disrupt the YAP-TEAD4 interaction and enhance biological activity in AML-related cellular models.
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GENOME BIOLOGY
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2025
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IF 9.4
Junhui Lv,Zhinang Yin,Conghui Li,Honglin Wen,Jian Ni,Peiyuan Yang,Zemin Song,Ying Xiang,Honghong Wang,Rui Lu,Li Huang,Ying Zhou,Hai-Bing Zhou,Ruijing Xiao,Pingping Fang,Kaiwei Liang
Background KAT6A-CBP (K/C) and KAT6A-P300 (K/P) fusions are recurrent genetic alterations in acute myeloid leukemia (AML) associated with poor prognosis. Despite their strong oncogenic potential, the mechanisms underlying their genomic targeting and leukemogenic function remain unclear. A major challenge has been their large size, which has impeded preclinical model development and mechanistic studies. Results We employ a domain-focused truncation strategy to generate de novo murine models of K/C and K/P fusions, which faithfully recapitulate the morphological, immunophenotypic, and transcriptomic features of KAT6A-rearranged AML. Genomic profiling reveals that KAT6A fusions preferentially localize to H3K4me2/3-marked regions, while biochemical analyses uncover that KAT6A interacts with the Nucleosome Remodeling Factor (NURF), a key H3K4me2/3 reader. Disrupting NURF-chromatin interactions via depletion or small-molecule inhibition of its subunit, Bromodomain PHD Finger Transcription Factor (BPTF), impairs K/C recruitment and disrupts MLL/COMPASS-mediated H3K4me2 deposition, defining a functional epigenetic module involving KAT6A chimeras, NURF, and MLL/COMPASS. Notably, CBP/P300 inhibition reduces histone acetylation and chromatin accessibility, further impairing the recruitment of this epigenetic module. Targeting this module via NURF or CBP/P300 inhibition demonstrates efficacy in K/C leukemia models, with enhanced therapeutic effects observed when combined. Conclusions Our study identifies a self-reinforcing epigenetic module of histone modifiers and readers in KAT6A-rearranged AML, providing mechanistic insights into the genomic targeting of KAT6A chimeras and highlighting promising combinatorial therapeutic strategies. Supplementary Information The online version contains supplementary material available at 10.1186/s13059-025-03743-y.
研究领域:
癌症生物学
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表观遗传学
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基因组学
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分子生物学
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血液学
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