1.Role and mechanism of histone deacetylases in mouse neuronal development.
Yu-Wei BAI ; Meng-Long GUAN ; Tao ZHENG ; Shi-Ping LI ; Yi QU ; De-Zhi MU
Chinese Journal of Contemporary Pediatrics 2021;23(3):294-299
OBJECTIVE:
To study the role and mechanism of histone deacetylase 1 (HDAC1) and histone deacetylase 2 (HDAC2) in mouse neuronal development.
METHODS:
The mice with Synapsin1-Cre recombinase were bred with
RESULTS:
The mice with
CONCLUSIONS
Deletion of
Animals
;
Blotting, Western
;
Histone Deacetylase 1/genetics*
;
Histone Deacetylase 2
;
Histone Deacetylases/genetics*
;
Immunohistochemistry
;
Mice
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Neurons/metabolism*
;
Signal Transduction
2.Effect of Histone Deacetylase Inhibition on the Expression of Multidrug Resistance-associated Protein 2 in a Human Placental Trophoblast Cell Line.
Hong-Yu DUAN ; Dan MA ; Kai-Yu ZHOU ; ; Tao WANG ; Yi ZHANG ; ; Yi-Fei LI ; Jin-Lin WU ; Yi-Min HUA ; ; Chuan WANG ;
Chinese Medical Journal 2017;130(11):1352-1360
BACKGROUNDPlacental multidrug resistance-associated protein 2 (MRP2), encoded by ABCC2 gene in human, plays a significant role in regulating drugs' transplacental transfer rates. Studies on placental MRP2 regulation could provide more therapeutic targets for individualized and safe pharmacotherapy during pregnancy. Currently, the roles of epigenetic mechanisms in regulating placental drug transporters are still unclear. This study aimed to investigate the effect of histone deacetylases (HDACs) inhibition on MRP2 expression in the placental trophoblast cell line and to explore whether HDAC1/2/3 are preliminarily involved in this process.
METHODSThe human choriocarcinoma-derived trophoblast cell line (Bewo cells) was treated with the HDAC inhibitors-trichostatin A (TSA) at different concentration gradients of 0.5, 1.0, 3.0, and 5.0 μmol/L. Cells were harvested after 24 and 48 h treatment. Small interfering RNA (siRNA) specific for HDAC1/HDAC2/HDAC3 or control siRNA was transfected into cells. Total HDAC activity was detected by colorimetric assay kits. HDAC1/2/3/ABCC2 messenger RNA (mRNA) and protein expressions were determined by real-time quantitative polymerase chain reaction and Western-blot analysis, respectively. Immunofluorescence for MRP2 protein expression was visualized and assessed using an immunofluorescence microscopy and ImageJ software, respectively.
RESULTSTSA could inhibit total HDAC activity and HDAC1/2/3 expression in company with increase of MRP2 expression in Bewo cells. Reduction of HDAC1 protein level was noted after 24 h of TSA incubation at 1.0, 3.0, and 5.0 μmol/L (vs. vehicle group, all P < 0.001), accompanied with dose-dependent induction of MRP2 expression (P = 0.045 for 1.0 μmol/L, P = 0.001 for 3.0 μmol/L, and P < 0.001 for 5.0 μmol/L), whereas no significant differences in MRP2 expression were noted after HDAC2/3 silencing. Fluorescent micrograph images of MRP2 protein were expressed on the cell membrane. The fluorescent intensities of MRP2 in the control, HDAC2, and HDAC3 siRNA-transfected cells were week, and no significant differences were noticed among these three groups (all P > 0.05). However, MRP2 expression was remarkably elevated in HDAC1 siRNA-transfected cells, which displayed an almost 3.19-fold changes in comparison with the control siRNA-transfected cells (P < 0.001).
CONCLUSIONSHDACs inhibition could up-regulate placental MRP2 expression in vitro, and HDAC1 was probably to be involved in this process.
Cell Line ; Histone Deacetylase 1 ; metabolism ; Histone Deacetylase 2 ; metabolism ; Histone Deacetylase Inhibitors ; pharmacology ; Histone Deacetylases ; metabolism ; Humans ; Hydroxamic Acids ; pharmacology ; Microscopy, Fluorescence ; Multidrug Resistance-Associated Proteins ; genetics ; metabolism ; RNA, Messenger ; Trophoblasts ; cytology ; metabolism
3.Efflect of miR-34a-Tangeted Regulation of HDACI on Apoptosis of AML Cells.
Chao WEN ; Yuan-Kang XIE ; Yi-Jian CHEN
Journal of Experimental Hematology 2019;27(3):790-795
OBJECTIVE:
To investigate the regulation of miR-34a on HDAC1 expression and its effect on the apoptosis of acute myeloid leukemia (AML) cells.
METHODS:
miR-34a mimics, miR-34a inhibitor and miR-34a scramble were transfected into HL-60 cells. The effects of miR-34a expression levels on proliferation and apoptosis of HL-60 cell were detected by CCK8 assay and flow cytometry respectively. The expression of HDAC1 protein was assessed by Western blot after regulating miR-34a expression, the 3'UTR of HDAC1 was cloned and ligated to construct a dual luciferase reporter vector, and then the dual luciferase reporter assay was applied to verify the target of miR-34a, the expression vector pcDNA3.1-HDAC1 was constructed, the interaction of miR-34a and HDAC1 was analyzed by reversion test.
RESULTS:
miR-34a over-expression could inhibit the proliferation of HL-60 cells and induce their apoptosis. Bioinformatics analysis indicated that the HDAC1 was a target gene of miR-34a. Western blot indicated that miR-34a overexpression down-regulated the expression of HDAC1. Dual luciferase reporter assay and reversion test showed that miR-34a could act at the 3-UTR of HDAC1 gene to regulate its expression.
CONCLUSION
miR-34a promotes the apoptosis of HL-60 cells via regulating HDAC1 expression.
Apoptosis
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Cell Proliferation
;
HL-60 Cells
;
Histone Deacetylase 1
;
metabolism
;
Humans
;
Leukemia, Myeloid, Acute
;
genetics
;
MicroRNAs
;
genetics
4.Effect of histone acetylation/deacetylation imbalances on key gene of planar cell polarity pathway.
Hong-Yu DUAN ; Yi ZHANG ; Kai-Yu ZHOU ; Chuan WANG ; DA-Jian QIU ; Yi-Min HUA
Chinese Journal of Contemporary Pediatrics 2017;19(4):475-483
OBJECTIVETo investigate the effect of histone acetylation/deacetylation imbalances on embryonic hearts of mice and its effect on key genes of planar cell polarity (PCP) pathway-Vangl2, Scrib and Rac1 in H9C2 cells.
METHODSForty pregnant C57/B6 mice were randomly assigned into three groups: blank group (n=10), vehicle group (n=10), and valproic acid (VPA)-treated group (n=20). In the VPA-treated group, VPA, a histone deacetylase (HDAC) inhibitor, was administered to each individual dam intraperitoneally at a single dose of 700 mg/kg on embryonic day 10.5 (E10.5). The vehicle and blank groups received equivalent saline or no interventions, respectively. Dams were sacrificed on E15.5, and death rates of embryos were evaluated. Subsequently, embryonic hearts of survival fetus were removed to observe cardiac abnormalities by hematoxylin-eosin (HE) staining. H9C2 cells were cultured and allotted to the blank, vehicle, and VPA-treated groups: the VPA treated group received VPA exposure at concentrations of 2.0, 4.0 and 8.0 mmol/L; the vehicle and blank groups received equivalent saline or no interventions, respectively. HDAC1-3 as well as Vangl2, Scrib and Rac1 mRNA and protein expression levels were determined by quantitative real-time PCR and Western blot, respectively. The total HDAC activity was analyzed by colorimetric assay.
RESULTSThe fetus mortality rate after VPA treatment was 31.7%, with a significantly higher rate of cardiac abnormalities in comparison with the controls (P<0.05). In comparison with the blank and vehicle groups, HDAC1 mRNA was significantly increased at various concentrations of VPA treatment at all time points of exposure (P<0.05), together with a reduction of protein level after 48 and 72 hours of exposure (P<0.05). The inhibition of HDAC2 mRNA after various concentrations of VPA incubation was pronounced at 24 hours of exposure (P<0.05), while the protein levels were reduced at all time points (P<0.05). HDAC3 mRNA was prominently induced by VPA (4.0 and 8.0 mmol/L) at all time points of treatment (P<0.05). In contrast, the protein level was inhibited after VPA treatment (P<0.05). In comparison with the blank and vehicle groups, Vangl2 mRNA as well as Scrib mRNA/protein expression levels were markedly reduced after 48 and 72 hours of VPA treatment (P<0.05), together with a reduction of protein level in Vangl2 at 72 hours (P<0.05). Compared with the blank and vehicle groups, a significant repression in the total HDAC activity was observed in the VPA-treated group at concentrations of 4.0 and 8.0 mmol/L after 24 hours of treatment (P<0.05), and the effect persisted up to 48 and 72 hours, exhibiting pronounced inhibition at all concentrations (P<0.05).
CONCLUSIONSVPA might result in acetylation/deacetylation imbalances by inhibiting HDAC1-3 protein expression and total HDAC activity, leading to the down-regulation of mRNA and protein expression of Vangl2 and Scrib. This could be one of the mechanisms contributing to congenital heart disease.
Acetylation ; Animals ; Cell Polarity ; Cells, Cultured ; Fetal Heart ; drug effects ; metabolism ; Heart Defects, Congenital ; etiology ; Histone Deacetylase 1 ; genetics ; Histone Deacetylase 2 ; genetics ; Histones ; metabolism ; Mice ; Mice, Inbred C57BL ; Nerve Tissue Proteins ; genetics ; RNA, Messenger ; analysis ; Valproic Acid ; pharmacology
5.Selective class I histone deacetylase inhibitors suppress persistent spontaneous nociception and thermal hypersensitivity in a rat model of bee venom-induced inflammatory pain.
Fan YANG ; Yan YANG ; Yan WANG ; Fei YANG ; Chun-Li LI ; Xiao-Liang WANG ; Zhen LI ; Jun CHEN
Acta Physiologica Sinica 2015;67(5):447-454
To confirm whether class I histone deacetylase inhibitors (HDACIs) are effective in relief of peripheral inflammatory pain, the effects of two selective inhibitors, MS-275 and MGCD0103, were studied in rats inflamed by subcutaneous (s.c.) injection of bee venom (BV). The BV test is characterized by displaying both persistent spontaneous nociception (PSN) and primary hypersensitivity. Intrathecal (i.t.) pre-treatment of either MS-275 or MGCD0103 with a single dose of 60 nmol/20 μL resulted in profound suppression of both PSN and primary thermal hypersensitivity but without significant influence upon the primary mechanical hypersensitivity and mirror-image thermal hypersensitivity. Moreover, the up-regulation of both HDAC1 and HDAC2 induced by s.c. BV injection was completely suppressed by i.t. pre-treatment of MS-275. The present results provide with another new line of evidence showing involvement of epigenetic regulation of chromatin structure by HDAC1/2-mediated histone hypoacetylation in the BV-induced PSN and thermal hypersensitivity and demonstrate the beneficial effects of class I HDACIs in prevention of peripheral inflammatory pain from occurring.
Animals
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Bee Venoms
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administration & dosage
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Benzamides
;
pharmacology
;
Epigenesis, Genetic
;
Histone Deacetylase 1
;
genetics
;
metabolism
;
Histone Deacetylase 2
;
genetics
;
metabolism
;
Histone Deacetylase Inhibitors
;
pharmacology
;
Hot Temperature
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Hyperalgesia
;
drug therapy
;
Inflammation
;
drug therapy
;
Injections, Subcutaneous
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Nociception
;
Pain
;
chemically induced
;
drug therapy
;
Pain Measurement
;
Pyridines
;
pharmacology
;
Pyrimidines
;
pharmacology
;
Rats
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Rats, Sprague-Dawley
;
Up-Regulation
6.Validation and Evaluation of Diagnostic Efficiency of Genes Associated with Colorectal Cancer with Hyperglycemia.
Ge CUI ; Wen Ming FENG ; Ting ZHANG ; Guo Liang ZHU ; Qi Lin SHI ; Xiao Lan ZHANG ; Hui XIA
Acta Academiae Medicinae Sinicae 2018;40(6):769-777
Objective To verify the expressions of genes associated with colorectal cancer with hyperglycemia and evaluate their diagnostic values.Methods Tumor tissues,distal normal intestinal mucosa,and peripheral blood samples were harvested from 109 colorectal cancer patients and peripheral blood samples from 30 diabetes patients and 30 healthy volunteers. The mRNA expressions of glucose regulated protein 78 (GRP78),NADPH oxidase-1 (NOX1),carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5),heat shock protein 60 (HSP60),and histone deacetylase 1(HDAC1) were detected by real-time quantitative polymerase chain reaction. The correlation between the gene expressions and clinicopathological parameters in colorectal cancer patients were analyzed using Pearson's correlation analysis. Diagnostic test accuracy evaluation was used to calculate the sensitivity,specificity,accuracy,predictability,Youden index,and likelihood ratio of serum gene expressions in colorectal cancer patients,and the receiver operating characteristic (ROC) curves were drawn. The area under the ROC curve was calculated to evaluate the diagnostic efficiency of the combined detection of multiple genes.Results The mRNA levels of GRP78 (P=0.001),NOX1 (P=0.022),CEACAM5 (P=0.000),HSP60 (P=0.044),and HDAC1 (P=0.047) were positively correlated with the fasting blood glucose level. The mRNA expressions of NOX1 (P=0.000,P=0.008) and HDAC1 (P=0.000,P=0.037) in tissues and serum were significantly higher in colorectal cancer patients than in patients with normal blood glucose levels. The NOX1 mRNA expression was positively correlated with the diameter of colorectal cancer (P=0.013),and the HDAC1 mRNA expression was significantly correlated with the tumor site (P=0.049),depth of primary tumor invasion (P=0.025),and TNM stage (P=0.042). The areas under the ROC curves of NOX1,CEACAM5,and HDAC1 were 0.931,0.852,and 0.860 respectively (all P=0.000). The specificity,accuracy,and negative predictive value of NOX1,HDAC1 mRNA expression in colorectal cancer patients with hyperglycemia were all above 90%. The diagnostic sensitivity and specificity of the combined detection of NOX1,CEACAM5,and HDAC1 were 98.82% and 99.93%,respectively.Conclusion Combined detection of genes associated with colorectal cancer accompanied by hyperglycemia can improve the diagnostic efficiency of early screening.
Biomarkers, Tumor
;
genetics
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Carcinoembryonic Antigen
;
genetics
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Case-Control Studies
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Colorectal Neoplasms
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complications
;
diagnosis
;
genetics
;
Diabetes Mellitus
;
genetics
;
GPI-Linked Proteins
;
genetics
;
Heat-Shock Proteins
;
genetics
;
Histone Deacetylase 1
;
genetics
;
Humans
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Hyperglycemia
;
complications
;
diagnosis
;
genetics
;
NADPH Oxidase 1
;
genetics
;
ROC Curve
7.Effect of siRNA targeting HDAC1 gene on proliferation, apoptosis, histone acetylation, and histone methylation in gastric cancer cells in vitro.
Hanxu ZHUANG ; Xudong MA ; Yadong LAI ; Xiangnong XU ; Xiaozhong WANG
Journal of Southern Medical University 2014;34(2):246-250
OBJECTIVETo investigate the effect of silencing histone deacetylases 1 (HDAC1) gene by RNA interference on the proliferation, apoptosis and histone modulation in gastric cancer MGC-803 cell line.
METHODSThe optimal segment targeting HDAC1 gene was designed and transfected into MGC-803 cells by Lipofectamine TM2000. HDAC1 mRNA and protein in the transfected cells were detected by RT-PCR and Western blotting, respectively. The growth inhibition of MGC803 cells was evaluated by MTT assay and the cell apoptosis was detected with TUNEL assay. The expression of Bcl-2, procaspase-9, procaspase-3, c-Myc, histone acetylation of H3, H4, and histone methylation of H3K9 was detected by Western blotting.
RESULTSThe siRNA targeting HDAC1HDAC1 markedly suppressed mRNA expression, inhibited cell proliferation and induced apoptosis of MGC-803 cells in a concentration manner. Transfection of the cells with HDAC1 siRNA at 0, 30, 60, and 120 nmol/L for 24 h resulted in a cell apoptotic rate of (4.8∓2.7)%, (18.5∓3.5)%, (41.4∓4.3)%, and (59.2∓5.5)%, respectively, and caused down-regulation of the expressions of Bcl-2, proCaspase9, proCaspase3 and c-Myc, upregulation of histone acetylation of H3, H4, and down-regulation of histone methylation of H3K9.
CONCLUSIONSilencing HDAC1 gene expression with HDAC1 siRNA can promote histone H3 and H4 acetylation and inhibit histone methylation of H3K9 to suppress the proliferation and induce apoptosis of gastric cancer MGC-803 cells.
Acetylation ; Apoptosis ; Cell Line, Tumor ; Cell Proliferation ; Gene Silencing ; Gene Targeting ; Histone Deacetylase 1 ; genetics ; Histones ; metabolism ; Humans ; Methylation ; RNA Interference ; RNA, Small Interfering
8.Acetylation of hepatic histone H3 in rats with intrauterine growth retardation.
Xiao-Mei LIU ; Hai-Lan ZHANG ; Wei-Wei SONG ; Yi-Sheng JIAO ; Yan LU
Chinese Journal of Contemporary Pediatrics 2009;11(9):753-756
OBJECTIVETo investigate the effects of intrauterine growth retardation (IUGR) caused by malnutrition during pregnancy on the acetylation of histone H3 and expression of histonedeacetylase1(HDAC1) in the hepar of the adult offspring and to explore the relationship between them.
METHODSMale 8-week-old offspring from maternal protein-malnutrition dams were studied. The expression of HDAC1 mRNA in the hepar was measured by fluorescent quantization RT-PCR. The levels of hepatic nuclear HDAC1 protein and acetylation of histone H3/K9 were assessed by Western blot.
RESULTSThe hepatic HDAC1 mRNA expression in IUGR rats was reduced to 54% of that of normal control rats (t=2.042, p<0.05). A decline in nuclear expression of HDAC1 protein (438 +/- 47) was also noted when compared with normal controls (1,128 +/- 110) (t=2.179, p<0.05). In contrast, the percentage of acetylated histone H3/K9 in IUGR rats (17.3 +/- 1.6%) increased significantly compared with that of normal control rats (10.5 +/- 1.2%) (t=3.597, p<0.01). The level of acetylated histone H3/K9 was negatively correlated with the HDAC1 protein concentration (r=-0.781, p<0.01).
CONCLUSIONSIncreased hepatic acetylation of histone H3 in the IUGR offspring might be caused by decreased HDAC1 expression in nuclear protein. This may contribute to the transcription change of some genes in the hepar.
Acetylation ; Animals ; Female ; Fetal Growth Retardation ; metabolism ; Histone Deacetylase 1 ; analysis ; genetics ; Histones ; metabolism ; Liver ; metabolism ; Male ; Pregnancy ; RNA, Messenger ; analysis ; Rats ; Rats, Wistar
9.A polymorphism in the histone deacetylase 1 gene is associated with the response to corticosteroids in asthmatics.
Min Hye KIM ; Sae Hoon KIM ; Yook Keun KIM ; Soo Jong HONG ; Kyung Up MIN ; Sang Heon CHO ; Heung Woo PARK
The Korean Journal of Internal Medicine 2013;28(6):708-714
BACKGROUND/AIMS: Recent investigations suggest that histone deacetylase 1 (HDAC1) and HDAC2 may be target molecules to predict therapeutic responses to corticosteroids. We evaluated the effects of variation in HDAC1 and HDAC2 on the response to corticosteroids in asthmatics. METHODS: Two single nucleotide polymorphisms (SNPs) were selected after resequencing HDAC1 and HDAC2. For the first analysis, we evaluated the association between those SNPs and asthma severity in 477 asthmatics. For the second analysis, we evaluated the effects of these SNPs on lung function improvements in response to corticosteroid treatment in 35 independent adult asthmatics and 70 childhood asthmatics. RESULTS: We found that one SNP in HDAC1 (rs1741981) was significantly related to asthma severity in a recessive model (corrected p = 0.036). Adult asthmatics who were homozygous for the minor allele of rs1741981 showed significantly lower % forced expiratory volume in 1 second (%FEV1) increases in response to systemic corticosteroids treatment compared with the heterozygotes or those homozygous for the major allele (12.7% +/- 7.2% vs. 37.4% +/- 33.7%, p = 0.018). Similarly, childhood asthmatics who were homozygous for the minor allele of rs1741981 showed significantly lower %FEV1 increases in response to inhaled corticosteroid treatment compared with the heterozygotes or those homozygous for the major allele (14.1% +/- 5.9% vs. 19.4% +/- 8.9%, p = 0.035). CONCLUSIONS: The present study demonstrated that rs1741981 in HDAC1 was significantly associated with the response to corticosteroid treatment in asthmatics.
Administration, Inhalation
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Adrenal Cortex Hormones/administration & dosage/*therapeutic use
;
Adult
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Aged
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Anti-Asthmatic Agents/administration & dosage/*therapeutic use
;
Asthma/diagnosis/*drug therapy/enzymology/genetics/physiopathology
;
Child
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Female
;
Forced Expiratory Volume
;
Gene Frequency
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Heterozygote
;
Histone Deacetylase 1/*genetics
;
Histone Deacetylase 2/genetics
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Homozygote
;
Humans
;
Lung/*drug effects/physiopathology
;
Male
;
Middle Aged
;
Pharmacogenetics
;
Phenotype
;
*Polymorphism, Single Nucleotide
;
Recovery of Function
;
Severity of Illness Index
;
Treatment Outcome
10.The evolving landscape in the therapy of acute myeloid leukemia.
Grace L PELOQUIN ; Yi-Bin CHEN ; Amir T FATHI
Protein & Cell 2013;4(10):735-746
Acute myeloid leukemia (AML) is a heterogeneous clonal disorder of myeloid precursors arrested in their maturation, creating a diverse disease entity with a wide range of responses to historically standard treatment approaches. While significant progress has been made in characterizing and individualizing the disease at diagnosis to optimally inform those affected, progress in treatment to reduce relapse and induce remission has been limited thus far. In addition to a brief summary of the factors that shape prognostication at diagnosis, this review attempts to expand on the current therapies under investigation that have shown promise in treating AML, including hypomethylating agents, gemtuzumab ozogamicin, FLT3 tyrosine kinase inhibitors, antisense oligonucleotides, and other novel therapies, including aurora kinases, mTOR and PI3 kinase inhibitors, PIM kinase inhibitors, HDAC inhibitors, and IDH targeted therapies. With these, and undoubtedly many others in the future, it is the hope that by combining more accurate prognostication with more effective therapies, patients will begin to have a different, and more complete, outlook on their disease that allows for safer and more successful treatment strategies.
Aminoglycosides
;
administration & dosage
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Antibodies, Monoclonal, Humanized
;
administration & dosage
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Elafin
;
genetics
;
Histone Deacetylase Inhibitors
;
therapeutic use
;
Humans
;
Isocitrate Dehydrogenase
;
Leukemia, Myeloid, Acute
;
drug therapy
;
genetics
;
pathology
;
Proto-Oncogene Proteins c-pim-1
;
metabolism
;
TOR Serine-Threonine Kinases
;
genetics