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1.
Journal of Experimental Hematology ; (6): 1034-1038, 2021.
Article in Chinese | WPRIM | ID: wpr-888515

ABSTRACT

OBJECTIVE@#To study the effects of FLT3-ITD length on 32D cell proliferation, apoptosis and sensitivity to FLT3 inhibitor, so as to provide references for stepwise therapy of FLT3-ITD mutated acute myeloid leukemia patients.@*METHODS@#Three different FLT3-ITD mutants with same or adjacent insert sites were selected and constructed in an eukaryotic expression vector. FLT3-ITD mutants stably expressed 32D cell strains were selected with the help of lentivirus system and IL3 free cell culture medium. The proliferation and apoptosis of 32D cell strains after AC220 treatment were detected.@*RESULTS@#FLT3-ITD mutants (ITD1, ITD2 and ITD3) stably expressed 32D cell strains were constructed successfully. In the absence of IL3 factor, the proliferation number of ITD1, ITD2 and ITD3 cell strains were mounted up to 2.3 folds, 3.7 folds, and 4.3 folds after 48 hours, respectively. Under the exposure of FLT3 inhibitor AC220, the IC@*CONCLUSION@#FLT3-ITD mutant expressed cell strains with longer ITD show higher capacity of proliferation and higher tolerance to AC220 treatment.


Subject(s)
Apoptosis , Cell Proliferation , Humans , Leukemia, Myeloid, Acute/genetics , Mutation , Protein Kinase Inhibitors , Tandem Repeat Sequences , fms-Like Tyrosine Kinase 3/genetics
2.
Article in Chinese | WPRIM | ID: wpr-880129

ABSTRACT

OBJECTIVE@#To investigate the expression of WTAP gene in acute myeloid leukemia (AML) and its clinical significance.@*METHODS@#74 acute myeloid leukemia patients with non-M3 type and 19 normal donors were selected, and real-time quantitative polymerase chain reaction was used to detect the mRNA expression level of WTAP gene in their bone marrow cells. The relationship between the mRNA expression level of WTAP gene and the clinical characteristics was analyzed.@*RESULTS@#The relative mRNA expression of WTAP gene in the non-M3 AML group was significantly higher than that in the healthy control group, and the difference showed statistically significant (P0.05) according to the classification of FAB. The mRNA expression level of WTAP gene in FLT3-ITD mutated AML patients was higher than that in FLT3-ITD unmutated group (P=0.016), and the mRNA expression level of WTAP gene in AML patients with CEBPα mutation was lower than that in CEBPα unmutated group (P=0.016). The expression level of WTAP mRNA was positively correlated with WT1 expression (r=0.6866, P0.05). The expression level of WTAP mRNA showed no obvious effect on the complete remission of patients after first treatment. The different expression level of WTAP gene at initial diagnosis showed also no effect on the overall survival time of patients.@*CONCLUSION@#The expression level of WTAP gene is increasing in new diagnosed non-M3 acute myeloid leukemia. There is a positive correlation between the expression level of WTAP gene and the expression level of WT1 fusion gene. WTAP mRNA always shows higher expression in patients with FLT3-ITD mutation than that in patients without FLT3-ITD mutation, and shows lower expression in patients with CEBPα mutation than that in unmutated group.


Subject(s)
Cell Cycle Proteins , Humans , Karyotype , Leukemia, Myeloid, Acute/genetics , Mutation , Prognosis , RNA Splicing Factors , Remission Induction , fms-Like Tyrosine Kinase 3/genetics
3.
Article in Chinese | WPRIM | ID: wpr-880090

ABSTRACT

OBJECTIVE@#To investigate the expression of CD73 in acute myeloid leukemia (AML) patients with NPM1 mutant and wild-type, and to evaluate the therapeutic efficacy and prognosis of CD73 to the AML patients.@*METHODS@#160 patients with AML treated in our hospital from June 2015 to June 2019 were enrolled, and 40 non-AML bone marrow samples from healthy people were selected as controls during the same period. The expression of CD73 in healthy people, NPM1 mutation and NPM1 wild-type AML patients were compared, and the relationship between the expression of CD73 and its clinicopathological characteristics, as while as efficacy in AML patients were analyzed. The patients were followed up, and the influence of CD73 to the prognosis of different AML patients was analyzed.@*RESULTS@#The positive expression rate of CD73 in AML patients (23.75%) was significantly higher than that in the healthy control group (0.62%), and the positive expression rate of CD73 in AML patients with NPM1 mutation (74.75%) was significantly higher than that with NPM1 wild-type (25.51%) (both P<0.001). AML patients with CD73 positive expression was associated with age, FAB typing, disease risk classification, and NPM1 gene mutation (both P<0.05). The overall survival rate of AML patients with NPM1 gene mutation was 75.98%, which was significantly higher than the patients with NPM1 wild-type (34.68%)(P<0.001), the median survival time of AML patients with NPM1 gene mutation in the CD73@*CONCLUSION@#The expression of CD73 was increased in AML patients with NPM1 gene mutation, and CD73 showed different prognostic significance in AML patients with different NPM1 gene mutation. The combination of clinicopathologic features, CD73 expression and NPM1 gene in AML patients is helpful to determine their prognosis and guide the formulation of relevant treatment plans.


Subject(s)
Humans , Leukemia, Myeloid, Acute/genetics , Mutation , Nuclear Proteins/genetics , Prognosis , Survival Rate , fms-Like Tyrosine Kinase 3
4.
Journal of Experimental Hematology ; (6): 1152-1156, 2020.
Article in Chinese | WPRIM | ID: wpr-827148

ABSTRACT

OBJECTIVE@#To study the clinical efficacy of allo-HSCT on FLT3-ITD positive AML patients.@*METHODS@#The clinical data and curative efficacy of 56 FLT3-ITD AML patients treated with allo-HSCT in our hospital from January 2012 to December 2018 were analyzed and evaluated.@*RESULTS@#Neutrophil implantation was successful for all the patients; The median time of granulocyte hematopoietic reconstruction and megakaryocyte hematopoietic reconstruction was 13 (10-20) d and 15 (9-23) d respectively. The median follow-up time for patients 34.3 (5.6-101.4) months, 41 patients were alive and 15 patients dead at the end of follow-up. The 3 years-OS and -DFS rate was 71.2% and 65.6%, respectively. Univariate analysis showed that the OS rate of patients without aGVDH (81.2±9.4)% was significantly higher than that of patients with aGVDH (55.4±9.1) % (χ=5.309,P<0.05). The OS rate of patients achieved CR after one chemotherapy course before allo-HSCT was (80.2±9.2)%, which was significantly higher than that of patients achieved CR after more chemotherapy courses (χ=4.275,P<0.05). Cox multivariate survival analysis showed that CR after more chemotherapy courses and aGVDH after transplantation were risk factors for OS rate.@*CONCLUSION@#Allo-HSCT can improve the prognosis of FLT3-ITD AML patients. The patients achieved CR after one chemotherapy course before allo-HSCT and patients without aGVDH after allo-HSCT have a better prognosis.


Subject(s)
Disease-Free Survival , Hematopoietic Stem Cell Transplantation , Humans , Leukemia, Myeloid, Acute , Prognosis , Remission Induction , Retrospective Studies , Treatment Outcome , fms-Like Tyrosine Kinase 3
5.
Journal of Experimental Hematology ; (6): 1183-1188, 2020.
Article in Chinese | WPRIM | ID: wpr-827142

ABSTRACT

OBJECTIVE@#To detect the expression levels of FAM19A5 in patients with mantle cell lymphoma (MCL), and to determine the relationship between FAM19A5 and the prognosis of MCL patients.@*METHODS@#Twenty-five MCL patients were choosen in the study, cytometric bead assay was used to detected the concentration of FAM19A5 in serum and immunohistochemical analysis were used to detect the expression levels of FAM19A5 in lymph nodes. The relationship of the FAM19A5 expression in serum and tissue were analyzed, the relationship of FAM19A5 and clinical characteristics of MCL patients, treatment and prognosis of MCL patients was analyzed.@*RESULTS@#The average serum concentration of FAM19A5 in MCL patients was 90.55±38.24 (ng/ml), which was significantly higher than that in control (P=0.0461). The proportion of high, medium, and low expression of FAM19A5 in lymph nodes was 32%, 36% and 32%, respectively, which showed significant difference from that in control group (P=0.001). The expression of FAM19A5 in serum and lymph nodes showed significant correlation (r=0.8683,P=0.001). The serum concentration of FAM19A5 showed positive correlation with the proportion of Ki67 (P=0.0222, r=0.4554). The mean survival time without relapse/death of MCL patients with high, middle and low expression of FAM19A5 was 17, 27 and 37.5 months, respectively,which showed significant statistical difference (P=0.0360). ROC curve analysis showed that serum concentration of FAM19A5 could predict the therapeutic effect in MCL patients, the cut-off value was 91.49 ng/ml. The proportion of recurrent/death in AML patients with FAM19A5 >91.49 ng/ml was significantly higher than that in patients with FAM19A5<91.49 ng/ml (P=0.0156).@*CONCLUSION@#The expression level of FAM19A5 is increased in MCL patient, and patients with high expression of FAM19A5 are more likely to relapse or die. FAM19A5 may be a new prognostic marker and potential therapeutic target for MCL.


Subject(s)
Adult , Hematopoietic Stem Cell Transplantation , Humans , Leukemia, Myeloid, Acute , Neoplasm Recurrence, Local , Prognosis , Treatment Outcome , fms-Like Tyrosine Kinase 3
6.
Article in Chinese | WPRIM | ID: wpr-829053

ABSTRACT

OBJECTIVE@#To investigate the clinical significance of AML patients with 11q23/MLL rearrangement, and to evaluate the effect of those mutations on the AML patients.@*METHODS@#53 cases involving translocations of chromosome 11q23 were identified by chromosome banding analysis. MLL rearrangements were detected by fluorescence in situ hybridization and/or multiplex nested PCR. The samples were screened for mutations in the candidate genes FLT3-ITD, FLT3-TKD, TET2, N-RAS, ASXLI, EZH2, DNMT3, C-Kit, NPM1, WT1, CEBPA by using genomic DNA-PCR and deep-sequencing.@*RESULTS@#21/53 MLL-rearranged AML cases showed at least one additional chromosomal aberrations. The most common additional aberration was +8. Gene mutations were observed in 23 cases (43.4%) and most cases showed singal mutation. N-RAS mutation was more frequent (8 cases, 15.1%), followed by WT1 mutation in 4 cases (7.5%), FLT3-ITD mutation in 3 cases, ASXL1 mutation in 2 cases, DNMT3A mutation in 2 cases, EZH2 mutation in 1 case, c-Kit17 mutation in 1 case, FLT3-TKD mutation in 1 case, and FLT3-ITD and TKD mutation coexistent in 1 case. No mutation was detected in CEBPA, NPM1, C-KIT8, TET2. Median OS for gene mutated patients was 8.5 months and 13 months for no mutated patients. Median OS for patients who received hematopoietic stem cell transplantation (HSCT) was 22.5 months and 7.5 months for patients who olny received chemotherapy.@*CONCLUSION@#A relatively high mutation frequency is observed in AML patients with 11q23/MLL rearrangements and most cases shows single mutation. The RAS signaling pathway alterations are most common. Gene mutation does not affect the OS of these patients, who show poor prognosis. A significantly higher Hb at initial diagnosis in FLT3 mutated patients is significantly higher than that in FLT3 wild-type cases. Patients who underwent HSCT show a better prognosis than those only received chemotherapy.


Subject(s)
Chromosomes, Human, Pair 11 , Hematopoietic Stem Cell Transplantation , Humans , In Situ Hybridization, Fluorescence , Leukemia, Myeloid, Acute , Mutation , Prognosis , fms-Like Tyrosine Kinase 3
7.
Article in Chinese | WPRIM | ID: wpr-829051

ABSTRACT

OBJECTIVE@#To compare the efficacy of haploidentical hematopoietic stem cell transplantation (hi-HSCT) HLA-matched sibling donor hematopoietic stem cell transplantation (MSD-HSCT) and post-remission chemotherapy (PR-CT) in treatment of intermediate risk acute myeloid leukemia with negative for FLT3-ITD, NPM1 or biallelic CEBPA mutation.@*METHODS@#The clinical data of patients with intermediate risk NPM1/non-CEBPA/FLT3-ITD AML from October 2009 to May 2016 were retrospectively analyzed.@*RESULTS@#The overall survival rate of the patients treated with PR-CT, MSD-HSCT or hi-HSCT was 63.7%, 71.7%, 75.5%, respectively (P<0.05); the disease-free survival (DFS) rate was 52.8%, 67.1%, 71.3% respectively (P<0.001); the cumulative incidence of relapse was 24.7%, 16.9%, 14.4% respectively (P<0.05); the non-relapse mortality was 26.2%, 17.3%, 14.4% reapectively (P>0.05). The analysis of transplantation, related adverse events showed that II-IV grade of aGVHD in the MSD-HSCT group and hi-HSCT group was 48.9% and 45.6% respectively (P>0.05); the extensive cGVHD event was 21.6% and 8.8% (P<0.05) respectively.@*CONCLUSION@#The efficiency of hi-HSCT and MSD-HSCT is superior to that of PR-CT for treatment of patients with intermediate risk NPM1/non-CEBPA/FLT3-ITD AML after CR1, there is no statistically significant difference in the efficiency of consolidatorg treatment and the transplantation-related mortality between hi-HSCT and MSD-HSCT.


Subject(s)
CCAAT-Enhancer-Binding Proteins , Hematopoietic Stem Cell Transplantation , Humans , Leukemia, Myeloid, Acute , Mutation , Nuclear Proteins , Prognosis , Retrospective Studies , fms-Like Tyrosine Kinase 3
8.
Frontiers of Medicine ; (4): 229-237, 2019.
Article in English | WPRIM | ID: wpr-771312

ABSTRACT

This retrospective analysis aimed to investigate the mutation profile of 16 common mutated genes in de novo acute myeloid leukemia (AML) patients. A total of 259 patients who were diagnosed of de novo AML were enrolled in this study. Mutation profiling of 16 candidate genes were performed in bone marrow samples by using Sanger sequencing.We identified at least 1 mutation in 199 of the 259 samples (76.8%), and 2 or more mutations in 31.7% of samples. FLT3-ITD was the most common mutated gene (16.2%, 42/259), followed by CEBPA (15.1%, 39/259), NRAS (14.7%, 38/259), and NPM1 (13.5%, 35/259). Concurrence was observed in 97.1% of the NPM1 mutated cases and in 29.6% of the double mutated CEBPA cases. Distinct patterns of co-occurrence were observed for different hotspot mutations within the IDH2 gene: R140 mutations were associated with NPM1 and/or FLT3-ITD mutations, whereas R172 mutations co-occurred with DNMT3A mutations only. Concurrence was also observed in 86.6% of epigenetic regulation genes, most of which co-occurred with NPM1 mutations. The results showed certain rules in the mutation profiling and concurrence of AML patients, which was related to the function classification of genes. Defining the mutation spectrum and mutation pattern of AML will contribute to the comprehensive assessment of patients and identification of new therapeutic targets.


Subject(s)
Adolescent , Adult , Aged , CCAAT-Enhancer-Binding Proteins , Genetics , Child , Child, Preschool , China , DNA Mutational Analysis , Female , GTP Phosphohydrolases , Genetics , Gene Expression Profiling , Gene Frequency , Genetic Predisposition to Disease , Humans , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute , Genetics , Male , Membrane Proteins , Genetics , Middle Aged , Mutation , Nuclear Proteins , Genetics , Phenotype , Retrospective Studies , Young Adult , fms-Like Tyrosine Kinase 3 , Genetics
9.
Article in Chinese | WPRIM | ID: wpr-775254

ABSTRACT

OBJECTIVE@#To investigate the expression of Wilms'tumor 1 () gene in patients with acute myeloid leukemia (AML), and to explore its application in predicting prognosis of AML in patients with wild or mutated nucleophosmin 1() and Fms-like tyrosine kinase 3-internal tandem duplication ().@*METHODS@#One hundred and sixty-seven newly diagnosed AML patients(exclued M3 type) were enrolled in this study. The survival of patients were analyzed with Kaplan-Meier method. The clinical data, laboratory findings and the survival of patients were analyzed and compared between patients with high expression (high- group) and those with low expression (low- group), as well as among the patients with or wild type and mutants.@*RESULTS@#The overall response rates (ORR) in high- and low- groups were 65.9% (83/126) and 95.1% (39/41), respectively (0.05). In patients with wild type, the high- group had inferior ORR and 2-y OS rate (all 0.05).@*CONCLUSIONS@# gene overexpression indicated poor prognosis of AML patients; the patients with decreased gene expression ≥ 1 log after the first induction therapy show better prognosis than those with<1 log. The gene expression level at diagnosis can be used as an unfavorable prognostic factor for AML patients with or wild types.


Subject(s)
Disease-Free Survival , Gene Expression Profiling , Humans , Kaplan-Meier Estimate , Leukemia, Myeloid, Acute , Diagnosis , Genetics , Mortality , Mutation , Nuclear Proteins , Genetics , Prognosis , WT1 Proteins , Genetics , fms-Like Tyrosine Kinase 3 , Genetics
10.
Journal of Experimental Hematology ; (6): 1820-1824, 2019.
Article in Chinese | WPRIM | ID: wpr-781534

ABSTRACT

OBJECTIVE@#To explore the efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of relapsed or refractory peripheral T-cell lymphoma(PTCL).@*METHODS@#The clinical data of 6 patients with relapsed or refractory PTCL undergoing allo-HSCT from Sep. 2014 to Sep. 2018 in the department of hematology, aerospace center hospital were retrospectively analyzed. Complications and disease-free survival after HSCT were observed.@*RESULTS@#All the patients could well tolerate the conditioning regimen and acquired hematopoietic recon-struction. Following up till December 2018, with a median time of 11.5 months (1-51); acute GVHD developed in 2 cases and chronic GVHD developed in 5 cases, Among 6 cases one case died of viral pheumonia and the other 5 patients remained disease-free survival. The longest disease-free survival time has reached 51 months.@*CONCLUSION@#allo-HSCT is a safe and effective method for relapsed or refractory peripheral T-cell lymphoma, which can be chosen as salvage treatment method for patients with primary resistance. Optimization of the conditioning regimen may result in better efficacy of allo-HSCT.


Subject(s)
DNA (Cytosine-5-)-Methyltransferases , Hematopoietic Stem Cell Transplantation , Humans , Leukemia, Myeloid, Acute , Mutation , Retrospective Studies , Transplantation Conditioning , fms-Like Tyrosine Kinase 3
11.
Journal of Experimental Hematology ; (6): 1088-1093, 2019.
Article in Chinese | WPRIM | ID: wpr-775759

ABSTRACT

OBJECTIVE@#To investigate the effects of inhibiting proliferation and inducing apoptosis of low-dose triptolide and sorafenib alone or in combination on FLT3-ITD acute myeloid leukemia cell line MV4-11 and STAT5 pathway.@*METHODS@#The MV4-11 cells were treated with low dose triptolide(IC) and sorafenib(IC) alone or in combination for 48 hours. The cell proliferation and inhibition were detected by using CCK-8 kit, the cell apoptosis was detected by flow cytometry, the expression of FLT3,STAT5 in mRNA and protein levels was detected by RT-PCR and Western blot respectively.@*RESULTS@#The treatment of MV4-11 cells with low dose triptolide and sorafenib alone and in combination for 48 hours could inhibit cell proliferation and induce cell apoptosis, moreover the inhibitory rate and apoptotic rate of MV4-11 cells in drug-combination group both were higher than those in single drug group. The mRNA expression and protein expression of FLT3,STAT5 signaling pathway in drug combination group were significantly lower than those in single drug group.@*CONCLUSION@#Low-dose triptolide combined with sorafenib can synergistically inhibit the proliferation and induce the apoptosis of MV4-11 cells, which may be related with the inhibition of FLT3 and STAT5 pathway.


Subject(s)
Apoptosis , Cell Line, Tumor , Diterpenes , Epoxy Compounds , Humans , Leukemia, Myeloid, Acute , Phenanthrenes , STAT5 Transcription Factor , Sorafenib , fms-Like Tyrosine Kinase 3
12.
Article in Chinese | WPRIM | ID: wpr-771970

ABSTRACT

OBJECTIVE@#To characterize the molecular genetics of 81 patients with acute monocytic leukemia (AML).@*METHODS@#Fluorescence in situ hybridization (FISH) was employed to detect MLL gene rearrangements. Combined mutations of 17 genes were detected by DNA-based PCR and Sanger sequencing.@*RESULTS@#Sixty seven patients were found to harbor at least one mutation. The most commonly mutated gene was NPM1 (n=18), which was followed by FLT3-ITD (n=16), NRAS (n=16), DNMT3A (n=15), TET2 (n=12), RUNX1 (n=11) and KRAS (n=9). Based on the functions of mutated genes, the most frequently involved genes were those involved in DNA methylation (38.27%), tyrosine kinase receptor signaling (32.1%), transcription regulation (28.4%), and RAS pathway (24.7%). Single gene mutation predominated in patient with cytogenetic abnormalities, while coexistence of 2 mutations have predominated in patient with normal cytogenetic findings. Stratified by cytogenetic findings, patients with single gene mutations (intermediate-risk group) had significantly higher complete remission (CR) rates than those with ≥2 gene mutations (unfavorable-risk group) (91.7% vs. 57.6% , 87.5% vs. 25.0%, P =0.0319, 0.0117, respectively).@*CONCLUSION@#Over 80% of AML patients were found to harbor at least one mutation. Their clinical phenotype and prognosis may be impacted by the synergy of MLL gene rearrangement and multiple mutations. For patients under the same risk stratification, the number of mutations is reversely correlated with the CR rate.


Subject(s)
Cytogenetics , Humans , In Situ Hybridization, Fluorescence , Leukemia, Monocytic, Acute , Leukemia, Myeloid, Acute , Mutation , Prognosis , fms-Like Tyrosine Kinase 3
13.
Article in Chinese | WPRIM | ID: wpr-771929

ABSTRACT

OBJECTIVE@#To explore the potential pathogenetic mutations of primary hypereosinophilia(HEN)by sequencing FGFR1 FLT3, MPL and JAK2 genes, and to clarify their effect on clinical manifestation and prognosis of HEN patients.@*METHODS@#The direct DNA sequencing was employed to detect the gene mutations of FGFR1, FLT3, MPL and JAK2 in HEN patients.@*RESULTS@#One deletion mutation (2654_2753del) within tyrosine kinase domain of FLT3 gene was found in a patient suffered from severe symptoms and ended with dismal outcome, which induced a premature stop codon (G885fsX888). For FGFR1, a new variation described as 1014_1019del AACAGT for nucleotide change was found in 19 cases, resulting in T339_V340del at the protein level.@*CONCLUSION@#The deletion of 6 bases in the FGFR1 gene (1014_1019del AACAGT) is first reported as non-synonymous SNP (nsSNP) site in the patients with primary hypereosinophilia. Deletion mutations in the FLT3 gene may be related with malignant clinical features and poor prognosis.


Subject(s)
Base Sequence , Humans , Hypereosinophilic Syndrome , Genetics , Mutation , Receptors, Thrombopoietin , Sequence Deletion , fms-Like Tyrosine Kinase 3
14.
Article in Chinese | WPRIM | ID: wpr-774308

ABSTRACT

OBJECTIVE@#To investigate the clinical features, accompanying gene mutation characteristics and prognostic factors of adult patients with acute myeloid leukemia with mutated NPM1 (NPM1AML).@*METHODS@#Seventy-three patients with newly diagnosed adult NPM1AML were selected. The mutations of 22 genes were detected by second generation sequencing and 43 fusion genes of AML were detected by real-time fluorescent quantitative PCR. The Kaplan-Meier survival curve and Cox multivariate regression analysis were used to study the prognostic factors.@*RESULTS@#A total of 74 NPM1 site mutations were detected in 73 patients with NPM1AML. The incidence rates were 92.0% L287fs, 2.7% Q289fs and W288fs, 1.4% L258fs and Q289H, among which 1 patient had 2 NPM1 mutations; the different mutation sites had no effect on the prognosis of NPM1AML. The median value of NPM1 variant allele frequency (VAF) was 35.4% (1.8%-56.6%). Based on the uppermost quartile of 38.4%, the patients were classified as NPM1 VAF>38.4% (NPM1AML) and NPM1 VAF≤38.4% (NPM1AML). Compared with NPM1AML, the early mortality rate was statistically significantly higher (33.3% vs 7.3%, P38.4% was an independent prognostic factor for EFS (HR=3.1, 95% CI 1.6-6.4, P<0.01) and OS (HR=3.0, 95% CI 1.4-6.2, P<0.01).@*CONCLUSION@#The NPM1 gene mutation in AML patients often is accompanied by other gene mutations, while the coexistence of fusion genes is rare; high NPM1 mutant allele burden is an independent prognostic factor for adult AML patients with mutated NPM1.


Subject(s)
Alleles , Humans , Leukemia, Myeloid, Acute , Genetics , Mutation , Nuclear Proteins , Genetics , Prognosis , fms-Like Tyrosine Kinase 3
15.
Article in Chinese | WPRIM | ID: wpr-774305

ABSTRACT

OBJECTIVE@#To investigate the effects of mangiferin on proliferation, apoptosis and cycle of FLT3-ITD mutation-positive acute myeloid leukemia cells and its mechanism.@*METHODS@#The effects of different concentration of mangiferin on proliferation of MV4-11 cells were detected by CCK8 method. Apoptosis, cell cycle and FLT3 transmembrane protein expression were detected by flow cytometry. FLT3 mRNA expression was detected by real-time fluorescent quantitative polymerase chain reaction (PCR) .@*RESULTS@#Mangiferin obviously inhibited MV4-11 proliferation in a concentration and time dependent manner (48 h,r=0.922;72 h,r=0.959;96 h,r=0.973). The ratio of G0/G1 phase in cell cycle increased with the enhancement of concentration of mangiferin in MV4-11 cells for 48 h, and the ratio of S phase decreased with enhasment of concentration. The increase of apoptosis was more obvious. The expression of FLT3 transmembrane protein significantly decreased after the actior of IC50 concentration of mangiferin in MV4-11 cells for 48 h. The results of qRT-PCR showed that the expression of FLT3 mRNA significantly decreased after treatment of MN4-11 cells with mangiferin (P<0.05).@*CONCLUSION@#Mangiferin inhibits MV4-11 cell proliferation, arrests cell cycle progression and promotes apoptosis, which may be related with the inhibition of FLT3 activity by mangiferin and the subsequent signaling pathways involved in apoptosis and proliferation of cells.


Subject(s)
Apoptosis , Cell Line, Tumor , Cell Proliferation , Humans , Leukemia, Myeloid, Acute , Mutation , Xanthones , fms-Like Tyrosine Kinase 3
16.
Cienc. Serv. Salud Nutr ; 9(2): 38-47, abr. 2018.
Article in Spanish | LILACS | ID: biblio-980643

ABSTRACT

Introducción: Los trastornos hipertensivos del embarazo siguen siendo una preocupación central de la salud pública en todo el mundo debido a que son una de las principales causas de mortalidad materna. Su tratamiento adecuado depende en gran medida del diagnóstico oportuno e intervención temprana. Objetivo: Identificar los principales biomarcadores para el diagnóstico temprano de los trastornos hipertensivos inducidos por el embarazo. Método: Se revisaron artículos científicos en MedLine, Pubmed, Cochrane, Scielo, entre otras bases de datos. Resultados y discusión: Niveles elevados de kinasa de tirosina símil FMS (sFtl-1), niveles bajos de factor de crecimiento placentario (PIGF) o factor de crecimiento endotetelial vascular (VEGF) libre y niveles altos de (PlGF/sFtl-1) tienen un alto valor predictivo positivo para el diagnóstico de preeclampsia. También parace demostrar resultados efectivos la combinación de ultrasonido doppler y niveles alterados de biomarcadores como proteína placentaria 13 (PP13) y endoglina soluble (sEng). Conclusiones: El uso de biomarcadores abre una nueva era en el diagnóstico y tratamiento de trastornos hipertensivos del embarazo.


Background: Hypertensive disorders of pregnancy constitute a public health concern throughout the world, mainly because they are one of the main causes of maternal mortality. Their adequate treatment depends on a great extent on an early diagnosis and oportune intervention. Objective: To identify the most important biomarkers for the early diagnosis of hypertensive disorders induced by pregnancy. Methodology: Review of academic articles available in MedLine, Pubmed, Cochrane, Scielo, among others. Results and discusión: Elevated levels of Fms-like tyrosine kinase 1 (sFtl-1), low levels of placental growth factor (PlGF) or free vascular endotelial growth factor (VEGF), and elevated levels of (PlGF/sFtl-1) have a high positive predictive value for the diagnosis of preeclampsia. Similarly, it seems equally efective the combination of doppler ultrasound and altered levels of biomarkers including placental protein 13 (PP13) and soluble endolgin (sEng). Conclusions: The use of biobarkers opens a new era for the early diagnosis and treatment hypertensive disorders of pregnancy.


Subject(s)
Humans , Female , Pregnancy , Pre-Eclampsia , Biomarkers , Hypertension, Pregnancy-Induced , fms-Like Tyrosine Kinase 3 , Placenta Growth Factor
17.
Article in Chinese | WPRIM | ID: wpr-690984

ABSTRACT

<p><b>OBJECTIVE</b>To investigate the clinical characteristics of acute myeloid leukemia(AML) patients with FLT3-ITD(Fms-like tyrosine kinase3, intenal tandem duplication) mutation and their response to treatment.</p><p><b>METHODS</b>Retrospective analysis of 128 newly diagnosed AML (except type M3) patients was performed between January 2014 and July 2017. Patients were divided into FLT3-ITD mutated group and non-mutated group. Mutation detection was carried out by using polymerase chain reaction(PCR) and gene sequencing analysis. Standard 3 + 7 or CAG regimen were taken as the first induction chemotherapy, 4 cases received sorafenib, overall survival (OS) was calculated by Kaplan-Meier.</p><p><b>RESULTS</b>Ninety-seven patients can be evaluable for clinical data available; 4 patients were FLT3-TKD mutated, which accounted for 4.1%; 19 patients were FLT3-ITD mutated, which accounted for 19.59%(19/97). Median white blood cell count (WBC), percentage of peripheral blasts and LDH value were significantly higher in FLT3-ITD group than those in non-mutated group [64.65(1.07-587.92)×10/L vs 39.68 (0.45-203.81) ×10/L](P<0.01), [69.62(16-99)% vs 36.35(0-92) %](P<0.01 ) and [LDH 526(124-2 729)U/L vs 265(20-1977)U/L](P<0.05), respectively. The frequency of coexisting NPM1 mutation was higher in FLT3-ITD group than that in non-mutated group [36.8(7/19)% vs 6.8 (5/74) %](P<0.01). The CR+PR was lower in FLT3-ITD group than that in non-mutated group [31.6(6/19)% vs 64.9 (48/74)%](P<0.05). OS in FLT3-ITD group was significantly shorter than that in non-mutated group (5 vs 18 months)(P<0.05). There is no significant difference in OS between FLT3-ITD concomitant with and without NPM1 mutation groups(5 vs 5 months)(P>0.05). The median OS was 13 months for the FLT3-ITD patients taking sorafenib.</p><p><b>CONCLUSION</b>The FLT3-ITD is a common mutation in AML, FLT3-ITD mutated AML is more likely concomitant with NPM1 mutation with higher number of WBC, percentage of peripheral blasts and LDH value, thus CR is low after the 1st treatment and survival is poor.</p>


Subject(s)
Humans , Leukemia, Myeloid, Acute , Mutation , Prognosis , Retrospective Studies , Tandem Repeat Sequences , fms-Like Tyrosine Kinase 3
18.
Article in Chinese | WPRIM | ID: wpr-690929

ABSTRACT

<p><b>OBJECTIVE</b>To explore the influence of FLT3-ITD mutation and ITD length on the overall survival (OS) and relapse free survival(RFS) in patients with non-M3 acute myeloid leukemia.</p><p><b>METHODS</b>Clinical features and therapeutic effect were retrospectively analyzed in 75 AML patients with FLT3-ITD mutation and 76 FLT3-ITD AML patients with a normal karotype from June 2011 to April 2016. Genomic DNA was amplified by PCR, and FLT3-ITD mutation length was analyzed by DNA sequencing in 40 patients.</p><p><b>RESULTS</b>AML patients with FLT3-ITD mutation had higher WBC count and the ratio of BM blast cells at initial diagnosis was also higher than those in AML patients without FLT3-ITD mutation (95.13 vs 10.85)(P<0.01); 72% vs 59%(P<0.01). The CR rates in AML patients with FLT3-ITD mutation less than those in AML patients without FLT3-ITD mutation(70.42% vs 94.7%)(P<0.01). OS (P<0.01) and RFS (P<0.01) were significantly increased in patients with AML who received allo-HSCT as compared with the patients who received consolidation chemotherapy and similar to AML patients without FLT3-ITD mutation who received HSCT. Patients with maintenance sorafenib after HSCT had longer OS (P<0.05) and RFS (P<0.05) than controls. ITDs exceeding 60 bp in length were associated with decreasing OS as compared with shorter ITD in AML patients with FLT3-ITD mutation (P<0.05). OS and RFS were similar among the 2 groups receiving consolidation chemotherapy. Besides, the patients with allo-HSCT had shorter ITDs and longer OS than ITDs exceeding 60 bp (P<0.05) and similar to AML patients without FLT3-ITD mutation.</p><p><b>CONCLUSION</b>AML patients with FLT3-ITD mutation has poorer outcome, among which the prognosis was worse in patients with ITD exceeding 60 bp, and the chemotherapy alone can not improve the prognosis of FLT3-ITD. Allo-HSCT is an effective treatment for AML patients with FLT3-ITD mutation; Sorafenib appears to be an effective maintenance therapy after allo-HSCT in FLT3-ITD AML.</p>


Subject(s)
Hematopoietic Stem Cell Transplantation , Humans , Leukemia, Myeloid, Acute , Mutation , Oncogene Proteins, Fusion , Prognosis , Retrospective Studies , fms-Like Tyrosine Kinase 3
19.
Article in Chinese | WPRIM | ID: wpr-689545

ABSTRACT

<p><b>OBJECTIVE</b>To analyze the clinical and laboratory features of acute myeloid leukemia (AML) with cuplike nuclei morphology.</p><p><b>METHODS</b>One hundred and seventy patients diagnosed with AML (M1andM2) between December 2009 and December 2016 were included in the study. Bone marrow smears were prepared for morphologic alanalysis, the immunophenotype was analyzed by flow cytometry and the RHG-banding was for conventional cytogenetic assay (CCA) ,gene mutation was detected by sequencing.</p><p><b>RESULTS</b>Among the 170 AMLpatients, 67 were diagnosed as M1 and 103 patients was diagnosed as M2, 43 patients(25.3%) defined as cuplike nuclei-positive, among them 38patients (88.4%) were M1 while only 5 patients (11.6%) were with M2(P<0.01). No significant value about sex(P> 0.05) between cuplike nuclei-positive and -negative group, while older patients were found in cuplike nuclei-positive group (P<0.05). Higher peroxydas (POX) ratio (P<0.05) and integration (P<0.05) were found in cuplike nuclei- positive group. Furthermore, the patients with cuplike nuclei-positive lack the expressions of CD34 (P<0.01) and HLA-DR(P<0.01) while no other immunophenotype markers were found. Among the 152 patients (89.4%) for genetic analysis ,83.8% karyotype of the cuplike nuclei-positive group were normal while only 54.8 of negative group was normal by CCA. Molecular biology analysis showed that the patients in cuplike nuclei-positive group have significantly highe rNMP1 (P<0.01) and FLT3(P<0.01) mutations as compared with the negative group. Furthermore, the relationship of the ratio o fcuplike nuclei and the type of gene mutations were investigated, and no significant associations were found. However, it was found that the patients with FLT3 mutation displayed more biological nuclear invagination than the patients with NPM1 mutations (P<0/01).</p><p><b>CONCLUSION</b>AML patients with positive cuplike nuclei have characteristic morphological changes, typical immunophenotype with HLA-DR- and CD34, normal karyotype accompanied by NPM1 and FLT3 mutations.</p>


Subject(s)
Cell Nucleus , Humans , Leukemia, Myeloid, Acute , Mutation , Nuclear Proteins , Prognosis , fms-Like Tyrosine Kinase 3
20.
Immune Network ; : e35-2018.
Article in English | WPRIM | ID: wpr-717670

ABSTRACT

Aryl hydrocarbon receptor (AhR) regulates both innate and adaptive immune responses by sensing a variety of small synthetic and natural chemicals, which act as its ligands. AhR, which is expressed in dendritic cells (DCs), regulates the differentiation of DCs. However, effects of AhR on the differentiation of DCs are variable due to the heterogeneity of DCs in cell surface marker expression, anatomical location, and functional responses. The plasmacytoid DCs (pDCs), one of DC subsets, not only induce innate as well as adaptive immune responses by secreting type I interferons and pro-inflammatory cytokines, but also induce IL-10 producing regulatory T cell or anergy or deletion of antigen-specific T cells. We showed here that AhR ligands indoxyl 3-sulfate (I3S) and indole-3-carbinol (I3C) inhibited the development of pDCs derived from bone marrow (BM) precursors induced by FMS-like tyrosine kinase 3 ligand (Flt3L). I3S and I3C downregulated the expression of signal transducer and activator of transcription 3 (STAT3) and E2-2 (Tcf4). In mice orally treated with I3S and I3C, oral tolerance to dinitrofluorobenzene was impaired and the proportion of CD11c⁺B220⁺ cells in mesenteric lymph nodes was reduced. These data demonstrate that AhR negatively regulates the development of pDCs from BM precursors induced by Flt3L, probably via repressing the expression of STAT3.


Subject(s)
Animals , Bone Marrow , Cell Differentiation , Cytokines , Dendritic Cells , Dinitrofluorobenzene , fms-Like Tyrosine Kinase 3 , Immune Tolerance , Interferon Type I , Interleukin-10 , Ligands , Lymph Nodes , Mice , Population Characteristics , Receptors, Aryl Hydrocarbon , STAT3 Transcription Factor , T-Lymphocytes , Vascular Endothelial Growth Factor Receptor-1
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