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Cellular Signalling Jun 2024Promyelocytic leukemia protein (PML), a tumor suppressor protein, plays a key role in cell cycle regulation, apoptosis, senescence and cellular metabolism. Here, we...
Promyelocytic leukemia protein (PML), a tumor suppressor protein, plays a key role in cell cycle regulation, apoptosis, senescence and cellular metabolism. Here, we report that PML promotes apoptosis and ferroptosis. Our data showed that PML over-expression inhibited cell proliferation and migration. PML over-expression increased apoptotic cells, nuclear condensation and the loss of mitochondrial membrane potential, accompanied by regulation of Bcl-2 family proteins and reactive oxygen species (ROS) level, suggesting that PML enhanced apoptosis. Meanwhile, PML over-expression not only increased lipid ROS accumulation and Malondialdehyde (MDA) content but also downregulated solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression, indicating that PML enhanced ferroptosis. Additionally, knockdown of p53 attenuated the effect of PML on SLC7A11 and GPX4, and inhibited the increase of lipid ROS and ROS by PML over-expression. Moreover, translocation of PML from nucleus to cytoplasm not only promoted apoptosis and ferroptosis, but also inhibited cell proliferation. Taken together, PML promotes apoptosis and ferroptosis, in which the mediation of p53 and the nuclear export of PML play important roles.
PubMed: 38944257
DOI: 10.1016/j.cellsig.2024.111278 -
ACS Infectious Diseases Jun 2024A newly discovered E3 ubiquitin ligase, UBR7, plays a crucial role in histone H2BK120 monoubiquitination. Here, we report a novel function of UBR7 in promoting hepatitis...
A newly discovered E3 ubiquitin ligase, UBR7, plays a crucial role in histone H2BK120 monoubiquitination. Here, we report a novel function of UBR7 in promoting hepatitis B virus (HBV) pathogenesis, which further leads to HBV-induced hepatocellular carcinoma (HCC). Transcriptomics analysis from HCC patients revealed the deregulation of UBR7 in cancer. Remarkably, targeting UBR7, particularly its catalytic function, led to a significant decrease in viral copy numbers. We also identified the speckled family protein Sp110 as an important substrate of UBR7. Notably, Sp110 has been previously shown to be a resident of promyelocytic leukemia nuclear bodies (PML-NBs), where it remains SUMOylated, and during HBV infection, it undergoes deSUMOylation and exits the PML body. We observed that UBR7 ubiquitinates Sp110 at critical residues within its SAND domain. Sp110 ubiquitination downregulates genes in the type I interferon response pathway. Comparative analysis of RNA-Seq from the UBR7/Sp110 knockdown data set confirmed that the IFN-β signaling pathway gets deregulated in HCC cells in the presence of HBV. Single-cell RNA-Seq analysis of patient samples further confirmed the inverse correlation between the expression of Sp110/UBR7 and the inflammation score. Notably, silencing of UBR7 induces IRF7 phosphorylation, thereby augmenting interferon (IFN)-β and the downstream interferon-stimulated genes (ISGs). Further, wild-type but not the ubiquitination-defective mutant of Sp110 could be recruited to the type I interferon response pathway genes. Our study establishes a new function of UBR7 in non-histone protein ubiquitination, promoting viral persistence, and has important implications for the development of therapeutic strategies targeting HBV-induced HCC.
PubMed: 38938101
DOI: 10.1021/acsinfecdis.4c00213 -
Journal of Pediatric Hematology/oncology Jun 2024Severe congenital neutropenia is an inherited bone marrow failure disorder characterized by profoundly low neutrophil counts and promyelocytic maturation arrest in bone...
Severe congenital neutropenia is an inherited bone marrow failure disorder characterized by profoundly low neutrophil counts and promyelocytic maturation arrest in bone marrow. Severe congenital neutropenia is most often caused by heterozygous ELANE mutations. In vitro and mouse xenograft studies using CRISPR/Cas9 have shown that introduction of frameshift/nonsense mutations in mutant ELANE may restore neutrophil counts, providing a model for gene therapy. Here, we present 2 children with inherited nonsense mutations in ELANE analogous to those proposed for gene therapy. Their normal peripheral blood neutrophil counts provide support for this approach through human "experiments of nature."
PubMed: 38934594
DOI: 10.1097/MPH.0000000000002908 -
Molecules (Basel, Switzerland) Jun 2024A series of phenyl -carbonyl selenides with o-ester functionality substituted on the oxygen atom with chiral and achiral alkyl groups was synthesized. All compounds are...
A series of phenyl -carbonyl selenides with o-ester functionality substituted on the oxygen atom with chiral and achiral alkyl groups was synthesized. All compounds are the first examples of this type of organoselenium derivatives with an ester substituent in the ortho position. The obtained derivatives were tested as antioxidants and anticancer agents to see the influence of an ester functionality on the bioactivity of -carbonyl selenides by replacing the -amide group with an -ester group. The best results as an antioxidant agent were observed for -((1,2,5)-(-)-2-isopropyl-5-methylcyclohexyl)-2-((2-oxopropyl)selanyl)benzoate. The most cytotoxic derivative against breast cancer MCF-7 cell lines was -(methyl)-2-((2-oxopropyl)selanyl)benzoate and against human promyelocytic leukemia HL-60 was -(2-pentyl)-2-((2-oxopropyl)selanyl)benzoate.
Topics: Humans; Antineoplastic Agents; Antioxidants; Esters; Organoselenium Compounds; MCF-7 Cells; HL-60 Cells; Structure-Activity Relationship; Molecular Structure
PubMed: 38930931
DOI: 10.3390/molecules29122866 -
International Journal of Molecular... Jun 2024All- retinoic acid (ATRA), the major active metabolite of all- retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread... (Review)
Review
All- retinoic acid (ATRA), the major active metabolite of all- retinol (vitamin A), is a key hormonal signaling molecule. In the adult organism, ATRA has a widespread influence on processes that are crucial to the growth and differentiation of cells and, in turn, the acquisition of mature cell functions. Therefore, there is considerable potential in the use of retinoids to treat diseases. ATRA binds to the retinoic acid receptors (RAR) which, as activated by ATRA, selectively regulate gene expression. There are three main RAR isoforms, RARα, RARβ, and RARγ. They each have a distinct role, for example, RARα and RARγ regulate myeloid progenitor cell differentiation and hematopoietic stem cell maintenance, respectively. Hence, targeting an isoform is crucial to developing retinoid-based therapeutics. In principle, this is exemplified when ATRA is used to treat acute promyelocytic leukemia (PML) and target RARα within PML-RARα oncogenic fusion protein. ATRA with arsenic trioxide has provided a cure for the once highly fatal leukemia. Recent in vitro and in vivo studies of RARγ have revealed the potential use of agonists and antagonists to treat diseases as diverse as cancer, heterotopic ossification, psoriasis, and acne. During the final drug development there may be a need to design newer compounds with added modifications to improve solubility, pharmacokinetics, or potency. At the same time, it is important to retain isotype specificity and activity. Examination of the molecular interactions between RARγ agonists and the ligand binding domain of RARγ has revealed aspects to ligand binding that are crucial to RARγ selectivity and compound activity and key to designing newer compounds.
Topics: Humans; Retinoic Acid Receptor gamma; Receptors, Retinoic Acid; Animals; Tretinoin; Protein Binding; Leukemia, Promyelocytic, Acute; Antineoplastic Agents
PubMed: 38928275
DOI: 10.3390/ijms25126568 -
International Journal of Molecular... Jun 2024We review the importance of monocytic differentiation and differentiation induction in non-APL (acute promyelocytic leukemia) variants of acute myeloid leukemia (AML), a... (Review)
Review
Monocytic Differentiation in Acute Myeloid Leukemia Cells: Diagnostic Criteria, Biological Heterogeneity, Mitochondrial Metabolism, Resistance to and Induction by Targeted Therapies.
We review the importance of monocytic differentiation and differentiation induction in non-APL (acute promyelocytic leukemia) variants of acute myeloid leukemia (AML), a malignancy characterized by proliferation of immature myeloid cells. Even though the cellular differentiation block is a fundamental characteristic, the AML cells can show limited signs of differentiation. According to the French-American-British (FAB-M4/M5 subset) and the World Health Organization (WHO) 2016 classifications, monocytic differentiation is characterized by morphological signs and the expression of specific molecular markers involved in cellular communication and adhesion. Furthermore, monocytic FAB-M4/M5 patients are heterogeneous with regards to cytogenetic and molecular genetic abnormalities, and monocytic differentiation does not have any major prognostic impact for these patients when receiving conventional intensive cytotoxic therapy. In contrast, FAB-M4/M5 patients have decreased susceptibility to the Bcl-2 inhibitor venetoclax, and this seems to be due to common molecular characteristics involving mitochondrial regulation of the cellular metabolism and survival, including decreased dependency on Bcl-2 compared to other AML patients. Thus, the susceptibility to Bcl-2 inhibition does not only depend on general resistance/susceptibility mechanisms known from conventional AML therapy but also specific mechanisms involving the molecular target itself or the molecular context of the target. AML cell differentiation status is also associated with susceptibility to other targeted therapies (e.g., CDK2/4/6 and bromodomain inhibition), and differentiation induction seems to be a part of the antileukemic effect for several targeted anti-AML therapies. Differentiation-associated molecular mechanisms may thus become important in the future implementation of targeted therapies in human AML.
Topics: Humans; Cell Differentiation; Leukemia, Myeloid, Acute; Mitochondria; Monocytes; Drug Resistance, Neoplasm; Molecular Targeted Therapy; Antineoplastic Agents
PubMed: 38928061
DOI: 10.3390/ijms25126356 -
Biomolecules May 2024DNA methylation plays an essential role in regulating gene activity, modulating disease risk, and determining treatment response. We can obtain insight into methylation...
DNA methylation plays an essential role in regulating gene activity, modulating disease risk, and determining treatment response. We can obtain insight into methylation patterns at a single-nucleotide level via next-generation sequencing technologies. However, complex features inherent in the data obtained via these technologies pose challenges beyond the typical big data problems. Identifying differentially methylated cytosines (dmc) or regions is one such challenge. We have developed DMCFB, an efficient dmc identification method based on Bayesian functional regression, to tackle these challenges. Using simulations, we establish that DMCFB outperforms current methods and results in better smoothing and efficient imputation. We analyzed a dataset of patients with acute promyelocytic leukemia and control samples. With DMCFB, we discovered many new dmcs and, more importantly, exhibited enhanced consistency of differential methylation within islands and their adjacent shores. Additionally, we detected differential methylation at more of the binding sites of the fused gene involved in this cancer.
Topics: DNA Methylation; Humans; Bayes Theorem; Epigenesis, Genetic; Leukemia, Promyelocytic, Acute
PubMed: 38927043
DOI: 10.3390/biom14060639 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the efficacy of decitabine combined with preexcitation regimen in the treatment of newly diagnosed acute myeloid leukemia (AML) patients who have not been...
OBJECTIVE
To investigate the efficacy of decitabine combined with preexcitation regimen in the treatment of newly diagnosed acute myeloid leukemia (AML) patients who have not been relieved by the first standard induction chemotherapy and its influence on the relative content of regulatory T lymphocytes (Tregs).
METHODS
The clinical data of 102 newly diagnosed AML patients (except acute promyelocytic leukemia) who did not relieve after initial standard induction chemotherapy in Shaanxi Provincial People's Hospital from March 2013 to March 2019 were retrospectively analyzed. Fifty-one patients who accepted pre-excitation regimen were divided into regular group, while another 51 patients treated with decitabine combined with pre-excitation regimen were divided into combination group. The efficacy, incidence of toxic and side effects, Core Scale of Quality of Life (QLQ-C30) score before and after treatment, T lymphocyte subsets (CD3, CD4, CD4/CD8, Tregs) and 3-year overall survival (OS) rate were compared between the two groups.
RESULTS
The total effective rate of combination group was 80.39%, which was significantly higher than 62.75% of regular group ( < 0.05). After treatment, the QLQ-C30 score of combination group was 60.27±6.96, which was significantly lower than 65.73±7.96 of regular group ( < 0.001). There was no statistical difference in the incidence of toxic and side effects between the two groups ( >0.05). After treatment, the levels of CD3, CD4, CD4/CD8 in the combination group were higher than those in the regular group (all < 0.001), while Treg was lower ( < 0.001). The 3-year OS rate in the combination group was 72.55%, which was significantly higher than 52.94% in the regular group ( < 0.001).
CONCLUSION
Decitabine combined with preexcitation regimen has a significant effect on AML patients who have not been alleviated by standard induction chemotherapy in the first course of treatment. It can reduce anti-tumor immune suppression and improve immune function by regulating the relative content of Tregs, thus prolongs survival time and improves life quality of patients without increasing adverse reactions.
Topics: Humans; Decitabine; Induction Chemotherapy; Retrospective Studies; Leukemia, Myeloid, Acute; T-Lymphocytes, Regulatory; Quality of Life; Male; Female; Treatment Outcome; Survival Rate
PubMed: 38926953
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.005 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the clinical significance, functional role and potential downstream mechanism of USP5 in acute myeloid leukemia (AML).
OBJECTIVE
To investigate the clinical significance, functional role and potential downstream mechanism of USP5 in acute myeloid leukemia (AML).
METHODS
The expression of in AML and normal tissues and its correlation with patients' survival were analyzed based on TCGA database. was knocked down and overexpressed in Jurkat and HL-60 cells using lentivirus. USP5 mRNA and protein expression were detected by RT-qPCR and Western blot, respectively. Cell proliferation and growth were measured by CCK-8 and methylcellulose colony-forming assay. Flow cytometry was used to analyze cell cycle and apoptosis.
RESULTS
was highly expression in AML compared with normal tissues. Up-regulation of was negatively correlated with the survival of AML patients. knockdown and overexpression inhibited and promoted the proliferation and colony growth of AML cells, respectively. Cell cycle arrest and apoptosis were induced in knockdown Jurkat and HL-60 cells. Furthermore, knockdown inhibited the phosphrylation of AKT, mTOR and 4EBP1.
CONCLUSION
Overexpression of predicts poor survival of AML patients. Targeting USP5 suppresses AKT/mTOR/4EBP1 signaling and reduces the proliferation and growth of AML cells.
Topics: Humans; Leukemia, Myeloid, Acute; Proto-Oncogene Proteins c-akt; Signal Transduction; TOR Serine-Threonine Kinases; Cell Proliferation; HL-60 Cells; Apoptosis; Adaptor Proteins, Signal Transducing; Cell Cycle Proteins; Jurkat Cells; Ubiquitin-Specific Proteases; Clinical Relevance
PubMed: 38926952
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.004 -
Zhongguo Shi Yan Xue Ye Xue Za Zhi Jun 2024To investigate the effect of expression regulated by miR-21 on proliferation and apoptosis of acute myeloid leukemia cells.
OBJECTIVE
To investigate the effect of expression regulated by miR-21 on proliferation and apoptosis of acute myeloid leukemia cells.
METHODS
Seventy patients with AML admitted to our hospital from January 2019 to July 2022 were selected, while 30 patients with iron deficiency anemia were selected as the control group. Bone marrow mononuclear cells (BMMNCs) of the patients were obtained using Ficoll density gradient centrifugation. RT-qPCR was used to determine the expression levels of and mRNA in BMMNCs. Mimics-miR-21, mimics-NC, inhibitor-miR-21, inhibitor-NC and NC were transfected into HL-60 cells using liposome-mediated transfection technology. CCK-8 method was used to determine the activity of transfected HL-60 cells after treatment with cytarabine. The apoptosis rate of HL-60 transfected cells was determined by TUNEL method. The expression of mRNA in HL-60 cells transfected with inhibitor-miR-21 was determined by RT-qPCR.
RESULTS
The relative expression levels of and mRNA in BMMNCs of AML patients were significantly higher than those of controls (both < 0.05). After HL-60 cells were treated with cytarabine, both the cell activity of inhibitor-miR-21 group and mimics-miR-21 group decreased significantly with the increase of cytarabine concentration (both < 0.05). However, at each concentration point of cytarabine, the cell activity of inhibitor-miR-21 group was lower than that of control group ( < 0.05), while mimics-miR-21 group was higher than control group ( < 0.05). After HL-60 cells were treated with cytarabine, the apoptosis rate of inhibitor-miR-21 group was significantly increased ( < 0.05), while that of mimics-miR-21 group was significantly decreased ( < 0.05). After HL-60 cells were treated with inhibitor-miR-21, the relative expression of mRNA decreased significantly ( < 0.05).
CONCLUSION
miR-21 is highly expressed in AML patients, which may promote the apoptosis of AML cells by inhibiting the expression of .
Topics: Humans; MicroRNAs; Leukemia, Myeloid, Acute; Apoptosis; Cell Proliferation; HL-60 Cells; Transfection; Cytarabine
PubMed: 38926950
DOI: 10.19746/j.cnki.issn.1009-2137.2024.03.002