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ABSTRACT: To study the potential role of Delta-like-1 (DLK1) in myelodysplastic syndromes (MDS), we carried out a series of experiments and found that DLK1 mRNA levels are dysregulated in patients with MDS or acute myelogenous leukemia (AML), and its overexpression leads to dysfunction of 32D and 3T3 cells. We conclude that DLK1 dysfunction may contribute to abnormal hematopoiesis of MDS and may be 1 of the antioncogenes. Delta-like-1 (DLK1) is frequently expressed at elevated levels in CD34(+) cells from patients with MDS. To investigate its role in the pathogenesis of MDS, we tested bone marrow samples from a panel of patients with MDS, AML, or myeloproliferative neoplasms, with real-time polymerase chain reaction (PCR). We show here that DLK1 mRNA levels are higher in MDS patients and lower in AML patients than in healthy individuals. Myeloid progenitor 32D cells overexpressing DLK1 display increased apoptosis, reduced differentiation, and decreased cell number expansion, which is also accompanied by changes in cell cycle progression. Immortalized fibroblastic 3T3 cells can grow into tumors in nude mice but the size of tumors are smaller from those overexpressing DLK1. These observations suggest that DLK1 dysfunction may contribute to the ineffective hematopoiesis of MDS.
Clinical lymphoma, myeloma & leukemia 04/2012; 12(4):261-8.
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ABSTRACT: To explore the frequencies of heterozygosity in X-linked G6PD, P55, BTK, and FHL-1 gene exonic polymorphic loci among Chinese females and the value of determination of hematopoietic clonality by detection of these X-chromosome exonic polymorphisms based on X-chromosome inactivation patterns (XCIP)-transcription-based clonality assays (TCA).
Genomic DNA was extracted from peripheral blood of 446 Chinese healthy females. Allele-specific PCR (ASPCR) or PCR-restriction enzyme digestion method was applied for detecting G6PD, P55, BTK and FHL-1 polymorphisms. Those heterozygotic loci were used as markers to examine the hematopoietic clonality of bone marrow mononuclear cells by TCA from essential thrombocythemia (ET) patients with JAK2V617F mutation and myelodysplastic syndrome (MDS) patients with abnormal karyotype.
Among the total 446 genomic DNA samples, the frequencies of heterozygosity in G6PD, P55, BTK and FHL-1 loci were 12.8%, 29.4%, 52.0% and 46.4%, respectively. About 81.4% of females were heterozygous at one or more loci. All 10 ET patients with JAK2V617F mutation and 2 MDS patients with abnormal karyotype, which were heterozygotic in either locus, had monoclonal/oligoclonal hematopoiesis.
Clonality detection based on X chromosome inactivation patterns-transcription based clonality assays is applicable to about 80% of Chinese females.
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 04/2012; 33(4):261-5.
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ABSTRACT: To investigate the impact of polymorphisms of DNA homologous recombination (HR) repair genes RAD51-G135C and XRCC3-C241T on the prognosis of acute myeloid leukemia (AML) with inv(16)/t(16;16)(CBFbeta-MYH1).
One hundred and three de novo inv(16)/t(16;16) (CBFbeta-MYH11) AML patients were followed-up and retrospectively analyzed. Polymorphisms of RAD51-G135C and XRCC3-C241T were detected by PCR-RFLP. The prognostic factors,including sex, age, white blood cell count, platelet count, hemoglobin level, karyotype, KIT mutation, RAD51-G135C and XRCC3-C241T polymorphisms at diagnosis, for complete remission (CR) achievement, overall survival (OS) and relapse-free survival (RFS) were analyzed by univariate and multivariate analyses.
The median follow-up of all patients was 28 (1 - 106) months. The overall CR rate was 92.2%. The estimated 5-year OS and RFS rates were 43.6% (95% CI 37.7% - 49.5%) and 26.4% (95% CI 21.1% - 31.7%), and the median OS and RFS were 53 (95% CI 133.4 - 72.7) and 27 (95% CI 22.9 - 31.1) months, respectively. In multivariate analysis, higher WBC (P = 0.004) and older than 30 years of age (P = 0.035) were independent poor factors for CR achievement, the XRCC3-241T variant (P = 0.007) and higher WBC (P = 0.009) were independent poor factors for 5-year RFS, and higher WBC (P = 0.002) and trisomy 8 (P = 0.035) were independent poor factors for 5-year survival. Polymorphism of RAD51-G135C had no significant impact on the prognosis.
The XRCC3-241T variant is an independent poor prognostic factor for AML with inv(16)/t(16;16)/CBFbeta-MYH11.
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 07/2011; 32(7):433-8.
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ABSTRACT: Folate metabolism plays an essential role in the processes of DNA synthesis and methylation. An aberrant folate metabolism caused by a genetic polymorphism may lead to genomic instability and affect the susceptibility to malignancies including acute lymphoblastic leukemia (ALL). This study was designed to explore the correlation between the polymorphisms in folate-related genes and the risk of ALL in Han Chinese. The DNA was isolated from 231 patients with pediatric ALL, 130 patients with adult ALL, and 367 healthy subjects (as controls). Polymorphisms were examined for RFC1 80G > A, DHFR 19 bp del/ins and 317A > G, SHMT1 1420C > T, MTHFR 677C > T and 1298A > C, MTR 2756A > G, MTRR 66A > G, TYMS 3R/2R, MTHFD1 1958G > A, and ABCG2 421G > T using real-time polymerase chain reaction (PCR) or PCR-restriction fragment length polymorphism (RFLP). The risk of adult ALL was increased by the RFC1 80AA variant (odds ratio [OR] = 2.09; 95% confidence interval [CI] 1.19-3.67) and MTRR 66GG variant (OR = 2.15; 95% CI 1.06-4.39) but reduced by the MTHFR 677TT variant (OR = 0.47; 95% CI 0.25-0.88), ABCG2 421GT variant (OR = 0.62; 95% CI 0.41-0.96), and ABCG2 421GT + TT variant (OR = 0.60; 95% CI 0.40-0.90). The increase in risk of adult ALL with the RFC1 80AA associated with the MTRR 66GG variant was even more significant (OR = 8.92; 95% CI 1.97-40.42). Furthermore, the MTHFR 677TT associated with the ABCG2 421GT + TT variant more significantly reduced the risk of adult ALL (OR = 0.32; 95% CI 0.12-0.85). However, all gene polymorphisms tested in this study failed to affect the pediatric ALL risk. Our study clearly demonstrates that polymorphisms in folate-related genes only modulate the susceptibility to adult ALL, but not to pediatric ALL, in Han Chinese.
Leukemia & lymphoma 06/2011; 52(9):1770-6. · 2.40 Impact Factor
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ABSTRACT: To investigate the relationship between DNA homologous recombination (HR) repair genes RAD51-G135C/XRCC3-C241T polymorphisms and development of acute myeloid leukemia (AML) with recurrent chromosome translocation.
Genomic DNA was extracted from bone marrow cells of 625 de novo AML patients and peripheral blood cells of 806 patient family members and 704 unrelated volunteers. Genotypes of RAD51-G135C and XRCC3-C241T were analyzed by PCR-RFLP. Cell lines with genotypes differed from XRCC3-C241T were selected and irradiated in vitro. The CBFβ-MYH11 fusion gene was detected by TaqMan real-time PCR.
The XRCC3-C241T variant (C/T + T/T) showed 6.22-fold and 6.99-fold increase in the risk of developing the AML with inv(16)/t(16;16)/CBFβ-MYH11 as compared with the volunteer and family member controls respectively; the RAD51-G135C homozygote-type (C/C) variant showed 0.87-fold (P = 0.010) and 1.15-fold (P = 0.001) respectively increase in the risk of this subtype AML. In the irradiated group, the CBFβ-MYH11 mRNA level in HL-60 cells was 59.49 times increased than that in KG1a cells. However, the RAD51-G135C and XRCC3-C241T variants had no correlations with the risk of development of t(15;17)/PML-RARα(+)AML, t(8;21)/AML1-ETO(+) AML and 11q23 AML subtypes.
The XRCC3-C241T variant and the RAD51-G135C homozygote-type significantly increase the risk of the development of AML with inv(16)/t(16;16)/CBFβ-MYH11.
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 05/2011; 32(5):299-303.
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ABSTRACT: DNA double-strand break repair via homologous recombination (HR) is essential in maintaining genetic integrity, and may modulate susceptibility to the development of acute myeloid leukemia (AML) and influence outcomes of AML. This study was designed to evaluate the effects of polymorphisms in HR repair genes RAD51 and XRCC3 on the risk and treatment outcomes of inv(16)/t(16;16)/CBFβ-MYH11(+) AML. The distribution of polymorphisms in RAD51-G135C and XRCC3-Thr241Met were studied by PCR-RFLP analysis in 625 cases of de novo AML, including 105 cases with inv(16)/t(16;16)/CBFβ-MYH11, 806 family controls and 704 volunteer controls. It was found that the XRCC3-241Met variant significantly increased the risk of the development of the AML with inv(16)/t(16;16) as compared with both the volunteer control (OR=7.22; 95% CI, 4.37-11.91) and the family control (OR=7.99; 95% CI, 5.03-12.69). A retrospective study conducted in 103 inv(16)/t(16;16) AML patients. In multivariate analysis for the potential prognostic factors, the XRCC3-241Met variant significantly reduced disease-free survival (DFS) in complete remission (CR) achieved patients (HR=2.34, 95% CI, 1.32-4.16). These data indicate that the XRCC3-241Met variant may not be only a susceptibility factor to the AML with inv(16)/t(16;16), but also an independent poor-prognostic factor for this AML subtype.
Leukemia research 02/2011; 35(8):1020-6. · 2.36 Impact Factor
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ABSTRACT: The incidence of HFE gene mutations in myelodysplastic syndrome (MDS) cases remains controversial. In this study, we examined the HFE C282Y and H63D mutations in 271 Chinese patients with MDS, 402 with aplastic anemia (AA) and 1,615 healthy controls by polymerase chain reaction-restriction fragment length polymorphism in combination with DNA sequencing. No C282Y mutations were observed in the entire cohort. The distribution of H63D heterozygous and homozygous genotypes was not significantly different between the AA cases and the controls (9.7% versus 10.2%, 0.25% versus 0.24%, respectively). While the H63D heterozygous genotype in MDS patients was significantly lower than that in the controls (4.1% versus 10.2%, p = 0.002), the H63D homozygous genotype was not detected in the MDS patients. The results suggest that HFE gene mutations are not common genetic factors in Chinese patients with MDS and AA. We also compared iron metabolic parameters, including serum ferritin, serum iron, and transferrin saturation values, between HFE mutant and HFE wild-type groups in the absence of transfusion iron overload, but no significant difference was found in either MDS or AA patients except that the level of serum iron in AA patients was significantly higher in mutant carriers than in those with wild-type HFE (p = 0.011). Similarly, there was no significant difference between HFE mutant and HFE wild-type MDS and AA patients in clinical indices such as alanine aminotransferase, aspartate aminotransferase, fasting blood sugar values, and electrocardiogram. The results suggest that H63D mutations may not have clinical significance in Chinese patients with MDS and AA.
Annals of Hematology 12/2010; 89(12):1249-53. · 2.62 Impact Factor
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ABSTRACT: Molecular epidemiological studies have found new insights into the etiology of myelodysplastic syndromes (MDS). We analyzed the polymorphisms of 5 genes in 275 patients with primary MDS and 354 healthy controls in an attempt to identify candidate genetic risk factors for primary MDS in Chinese Han population. There was no difference in polymorphic variants of GSTM1, NQO1-C609T and XRCC3-C241T between the patients and controls. The homozygous variant C/C of RAD51-G135C was found to increase the susceptibility to MDS (OR, 4.13; p=0.001) and the risk of MDS association with structural abnormal karyotype (OR, 7.67; p=0.001). In addition, the null genotype of GSTT1 was correlated MDS patients with complex aberrant karyotype (OR, 3.25; p=0.012). These potential genetic predisposition suggested their possible involvement in the multistep pathogenesis of MDS.
Leukemia research 12/2010; 35(6):762-5. · 2.36 Impact Factor
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ABSTRACT: OBJECTIVE: To investigate NPM1 gene mutations in patients with primary myelodysplastic syndromes (MDS) and the clinical characteristics of patients with NPM1 mutants. METHODS: Genomic DNA corresponding to exon 12 of NPM1 gene was amplified by polymerase chain reaction (PCR) in 232 patients with primary MDS. Identification of mutants was by direct sequencing and classification of mutation types by sequencing followed by plasmid cloning. RESULTS: NPM1 mutants were found in 9 patients (3.9%). All the mutants were type A. As compared with those with NPM1 wild type, patients with the mutant were of lower ANC \[0.60 (0.12 - 2.91) × 10(9)/L vs 1.02 (0 - 10.23) × 10(9)/L, P = 0.046\], higher blast percent in bone marrow \[0.050 (0 - 0.090) vs 0.025 (0 - 0.190), P = 0.035\], decreased BFU-E \[0 (0 - 0)/10(5) BMMNC vs 6 (0 - 40)/10(5) BMMNC, P = 0.038\] and increased serum vitamin B(12) \[936.40 (373.80 - 2400.00) pmol/L vs 557.85 (17.00 - 3032.10) pmol/L, P = 0.045\] The chromosomal karyotypes of patients with NPM1 mutant were predominantly normal. CONCLUSION: MDS patients with NPM1 gene mutations have some unique clinical and laboratory features. The results give new hint for the pathogenesis of MDS development and progression.
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 12/2010; 31(12):809-812.
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ABSTRACT: To survey the frequencies and characteristics of polymorphism of seven genes coding drug-metabolizing enzymes in a Han Chinese population.
Genomic DNA was extracted from peripheral blood in 1382 unrelated Han Chinese volunteers. Genotypes of CYP450, NQO1, MPO, MTHFR, NAT2, TPMT*3B(G460A) and TPMT*3C(A719G) were analyzed by PCR-RFLP. GSTM1 and GSTT1 genotypes were detected by multiple PCR and TPMT*2(G238C) genotypes by allele-specific PCR.
The allele frequencies of wild-type, heterozygosity and homozygosity were 99.8%, 0.2% and 0 in CYP3A4*1B genotypes, 8.4%, 34.3% and 57.3% in CYP3A5*3 genotypes, 28.7%, 49.7% and 21.6% in NQO1(C609T) genotypes, 75.0%, 23.2% and 1.8% in MPO(G463A) genotypes, 25.9%, 44.9% and 29.2% in MTHFR(C677T) genotypes, 67.3%, 30.4% and 2.3% in MTHFR(A1298C) genotypes, and 96.8% 3.2% and 0 in TPMT*3C(A719G) genotypes, respectively. The frequencies of present and null genotypes were 36.1% and 63.9% in GSTM1, 54.4% and 45.6% in GSTT1 respectively. The frequencies of NAT2*4/*4, *4/*5, *4/*6, *4/*7, *5/*5, *5/*6, *5/*7, *6/*6, *6/*7 and *7/*7 genotypes were 34.5%, 4.3%, 24.3%, 18.2%, 0.1%, 1.8%, 1.5%, 5.0%, 7.6% and 2.6% respectively. The frequencies of specific NAT2 alleles were 57.9%, 3.9%, 21.8% and 16.3% for NAT2*4, *5, *6 and *7 respectively. The frequencies of genophenotypes were 81.4% and 18.6% in NAT2 fast acetylator and low acetylator respectively. The allele frequency of wild type were 100% in both TPMT*2(G238C) genotypes and TPMT*3B(G460A). The variant alleles of TPMT*2(G238C) and TPMT*3B(G460A) were not found in 1382 Han Chinese subjects.
Significant differences in the distributions and frequencies in genetic polymorphisms of drug-metabolizing enzymes are identified between Han Chinese population and Caucasians, as well between Han Chinese population and Melanoderma while only some heterogeneity has been observed between Han Chinese population and other Xanthoderms in Asia.
Zhonghua yi xue za zhi 10/2009; 89(38):2675-81.
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ABSTRACT: This study was purposed to investigate the relationship between NQO1C(609T), RAD51(G135C), XRCC3(C241T) single nucleotide polymorphisms and incidence of acute lymphoblastic leukemia (ALL). NQO1C(609T), RAD51(G135C), XRCC3(C241T) genotypes were detected by PCR-RFLP in 170 patients with de novo ALL and 458 normal persons as control. The results indicated that the genotype ratio of NQO1C(609T), RAD51(G135C) and XRCC3(C241T) in single genotype analysis showed no statistical difference between ALL patients and normal controls, which suggested that the single genotype affect onset of ALL without statistical significance. In combined genotype analysis, presence of both variants for NQO1C(609T) and RAD51(G135C) increased onset risk of ALL with myeloid antigen positive and with balanced translocation (OR value 5.553 and 2.618 respectively); the presence of homozygosity variant for NQO1C(609T) increased onset risk of ALL in the country-children (OR = 2.541). In conclusion, the combined effect of NQO1C(609T), RAD51(G135C) and XRCC3(C241T) genotypes may promote occurrence of ALL, which suggests that the combined analysis of 3 genotypes has more predictive significance for ALL than single genotype analysis.
Zhongguo shi yan xue ye xue za zhi / Zhongguo bing li sheng li xue hui = Journal of experimental hematology / Chinese Association of Pathophysiology 07/2009; 17(3):523-8.
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ABSTRACT: To detect the incidence of the HFE gene C282Y and H63D mutations in patients with myelodysplastic syndromes (MDS) and aplastic anemia (AA), and analyze the relationship of these mutations with iron metabolism, and organs impairment from iron overload.
The incidence of the C282Y and H63D mutations in 271 MDS, 402 AA patients and 1615 normal subjects was measured by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) combining with DNA sequencing. Iron metabolism parameters and iron overload indices were retrospectively compared between HFE gene mutation and unmutation groups in MDS and AA patients with no transfusion history.
No C282Y and C282Y/H63D compound mutation was detected in all the three groups. The incidence of H63D heterozygous and homozygous genotype did not significantly differ between AA cases and controls (9.7% vs 10.2%, 0.25% vs 0.24% respectively, both P > 0.05). The frequency of H63D heterozygous genotype in MDS patients was significantly lower than that in controls (4.1% vs 10.2%, P = 0.002). H63D homozygous was not found in MDS patients. In both MDS and AA patients with no RBC transfusion history, serum ferritin (SF), transferrin saturation value (TS), serum iron concentration (SI) were close to or higher than normal; and unsaturated iron-binding capacity (UIBC) value was significantly lower. There was no significant difference in SF, SI, TS values between HFE-mutation and -unmutation MDS patients. For AA patients, only the level of SI was significantly higher in HFE-mutant group than in -unmutation group [42.6 (24.6-60.4) micromol/L vs 32.0 (8.4-63.3) micromol/L, P = 0.011]. There was no significant difference in the values of liver enzyme, fasting blood sugar (FBS), abnormal electrocardiogram (ECG), peripheral blood indices between HFE-mutation and -unmutation MDS and AA groups (all P > 0.05).
The distribution of C282Y and H63D mutations has ethnic and genetic disparity, the frequency in Chinese population is lower than that in Caucasian. It seems that MDS and AA patients are susceptible to iron overload, in the diseases itself and the mutations of HFE gene are not the major factor for iron overload in the patients.
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 04/2009; 30(4):223-8.
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ABSTRACT: We investigated the prognostic significance of genetic polymorphism for glutathione S-transferase theta 1 (GSTT1) and glutathione S-transferase mu 1 (GSTM1) in 254 Chinese patients with de novo acute myeloid leukemia (AML) other than AML-M3. The early death rate after the initiation of chemotherapy was similar between the GSTT1+/GSTM1+ group and GSTT1-/GSTM1- group. The complete remission (CR) rate was higher in GSTM1+ group than in GSTM1- group (OR=1.88; P=0.03) after the first course of chemotherapy, and was higher in GSTT1+ group than in GSTT1- group (OR=2.20; P=0.02) after the second course of chemotherapy. Overall survival and disease-free survival of CR patients in GSTT1 and GSTM1 double present group was better than in GSTT1- and/or GSTM1-group (P=0.03 and 0.02, respectively). Our preliminary results warrant testing of a larger number of patients.
Leukemia Research 09/2008; 32(8):1288-91. · 2.92 Impact Factor
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Haematologica 06/2008; 93(5):787-8. · 6.42 Impact Factor
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ABSTRACT: To investigate JAK2V617F mutation and its clinical significance in patients with chronic myeloproliferative disorders (cMPD).
A retrospective study was performed on 523 cMPD patients diagnosed according to the current World Health Organization (WHO) criteria. Allele-specific PCR (ASP) was used to identify JAK2V617F mutation, the mutation status was analyzed by PCR-RFLP, and the results were confirmed by sequence analysis. The mutation burden was calculated by the ratio of T/G. The correlation between the allele burden and the clinical and hematologic features was analysed. For those without JAK2 V617F, MPL W515L mutation was analyzed.
JAK2 V617F was detected in 66% of all patients (94% in PV, 80% in ET, 78% in CIMF, 75% in CMPD-U and 14% in HES). The majority of patients carried JAK2 V617F mutation were heterozygous , homozygote was found in only 5 cases (4 in PV and 1 in ET). The mutation burden in most patients (71.5%) was low with PV>ET>CIMF (P =0.003). Hemoglobin level was significantly related to high mutation burden in PV (r = 0. 203, P =0.033). Bone marrow megakaryocyte counts were found to be marked increased in ET with high JAK2 V617F loads (P = 0.024), and hepatomegaly in CIMF was significantly associated with high JAK2 V617F mutation burden (r = 0.315, P = 0.001).
1) Most cMPD patients, especially those with PV, carry JAK2 V617F mutation, except for CML. 2) .98% of JAK2 V617F mutation occurs of heterozygous status. 3) The mutation burden is PV>FT>CIMF. High JAK2 V617F loads are significantly associated with higher hemoglobin level in PV and higher bone marrow megakaryocyte counts in ET. 4) The positive correlation between hepatomegaly and JAK2 V617F mutation burden is found in CIMF.
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 03/2008; 29(2):105-9.
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ABSTRACT: To investigate the clinical and laboratory features of chronic eosinophilic leukemias (CEL) and hypereosinophilic syndrome (HES).
The clinical manifestations, laboratory parameters were retrospectively analyzed in 20 patients with HES/CEL. Detection of the FIP1L1-PDGFRA fusion gene was performed by nested RT-PCR. JAK2 V617F mutation screening was processed through allele-specific PCR combined with sequence analysis. PCR-RFLP was used to discriminate homozygous from heterozygous mutation patterns. TCR gamma rearrangement was detected by PCR.
Of the 20 patients, 19 were males and one female, with a median age of 33 (20 to 57) years. The FIP1L1-PDGFRA fusion gene positivity in bone marrow mononuclear cells in 12 cases was identified. All the breakpoints were identified by direct sequencing of cloned RT-PCR products in FIP1L1 intron 10 - 12 and in PDGFRA exon 12. In CEL the most common involved organs were lungs, heart and nervous system. Splenomegaly was significantly more frequent in CEL than in HES (92.5% vs 42.5%, P = 0.031). Anemia and myelofibrosis were common in CEL. There was no significant difference in circulating absolute eosinophil, leukocyte, platelet counts, hemoglobin level and percentages of eosinophil and blast cell in bone marrow between CEL and HES. The morphological abnormalities of eosinophils on bone marrow smear were easily found in CEL, including hypogranularity, and cytoplasmic vacuolization, increased basophilic granule. One patient with HES was found to have heterozygous JAK2 V617F mutation. Six patients had TCR gamma rearrangement, including 4 CEL and 2 HES.
(1) There is a male predominance in HES/CEL, and the median age was in the thirties. (2) The most common involved organs in CEL were lung, heart and nervous system. Bone marrow morphology might be of a little help in diagnosis of CEL. (3) JAK2 V617F may be involved in the pathogenesis of HES. (4) Patients with CEL carried the FIP1L1-PDGFRA fusion gene and TCR gamma rearrangement concurrently, their relationship warrants further study.
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 02/2008; 29(1):3-8.
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ABSTRACT: To investigate the impacts of RAD51G(135C) and XRCC3(C241T) genotypes on the response, adverse effects, and prognosis of acute myelocytic leukemia (AML).
RAD51(G135C), XRCC3(C241T), GSTT1, and GSTM1 genotypes were analyzed in 372 patients with AML, 226 males and 146 females, by PCR-RFLP or PCR. The Complete remission (CR) rate, adverse effects, overall survival (OS), and relapse-free survival (RFS) were compared among the groups with different genotypes.
(1) During the induction chemotherapy, XRCC3(C241T) polymorphic allele was significantly associated with the shorter survival of the AML patients with t (15; 17)/PML-RARalpha (OR = 8.750, P = 0.046). Among the non-M3 patients, the complete remission (CR) rate of those with double RAD51(G135C) and GSTT1 wild genotypes was 71.6%, significantly higher than that of those not with double RAD51(G135C) and GSTT1 wild genotypes (54.4%, P = 0.028). (2) The OS of the non-M3 AML patients with double RAD51(G135C) and GSTT1 wild genotypes was (39.1 +/- 7.1) months, significantly longer than those with double variant types [(22.4 +/- 3.2) months, P = 0.042]. The relapse-free survival (RFS) of the M4EO and M2 patients with double XRCC3(C241T) and GSTT1 wild type genotype were 48.3 months and 56.5 months, both significantly longer than those of the patients with double variant genotypes (28.8 months and 10.0 months respectively, both P < 0.05). The OS of the M2 patients with triple RAD51(G135C), GSTT1, and GSTM1 variant genotypes was (22.4 +/- 3.2) months, significantly shorter than those with triple RAD51(G135C), GSTT1, and GSTM1 wild genotypes [(39.1 +/- 7.1) months, P = 0.042]. The RFS of the M2 patients with triple RAD51(G135C), GSTT1, and GSTM1 variant genotypes was 10.0 months, significantly shorter than that of the patients with triple RAD51(G135C), GSTT1, and GSTM1 wild genotypes (64.2 months, P = 0.015). (3) The risk levels of neutropenia, nausea and vomiting, and alopecia of the patients with variant XRCC3(C241T) genotype were all significantly higher than those of the wild type genotype (all P < 0.05). The risk of hematuria of the patients with variant genotype was significantly higher than that of the patients with wild genotype (P = 0.017).
The polymorphisms of XRCC3(C241T) and RAD51(G135C) genes are significantly related to response to therapy, adverse effects, and prognosis of AML. Detection of the XRCC3(C241T) and RAD51(G135C) genotypes may be useful in selecting individual chemotherapy regimens for patients with AML.
Zhonghua yi xue za zhi 02/2008; 88(6):378-82.
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ABSTRACT: Mutations at exon 12 of the nucleophosmin (NPM1) gene are the most frequent acquired molecular abnormalities in adult and pediatric acute myeloid leukaemia (AML) with normal karyotype. We screened 28 patients with new diagnosed primary AML with normal karyotype, 38 patients with myelodysplastic symdromes (MDS) and 19 healthy volunteer for mutations at exon 12 of NPM1 gene. NPM1 mutations were identified in four AML patients and two MDS patients, including one novel sequence variant. As far as we know, this is the first report of NPM1 mutation in patients with MDS in the English literature until now, and our primary data support that NPM1 mutations may be also involved in the pathogenesis of MDS.
Leukemia Research 02/2007; 31(1):109-11. · 2.92 Impact Factor
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ABSTRACT: To investigate nucleophosmin (NPM) gene mutations in patients with de novo acute myeloid leukemia (AML) with normal cytogenetics and primary myelodysplastic syndromes (MDS).
Genomic DNA corresponding to exon 12 of NPM gene was amplified by polymerase chain reaction (PCR) in 40 AML patients (28 case untreated and 12 in first remission) and 33 MDS patients. The PCR products were purified and screened by direct sequencing, the mutation PCR products were cloned into pUCm-T vector and then transfected into E. coil DH5alpha. At least 5 recombinant colonies were selected, and plasmid DNA were prepared and sequenced.
NPM mutations were found in 6 patients (4 newly diagnosed AML and 2 MDS): 4 were type A,1 type B, and 1 novel sequence variant ( named as type R).
A new type of NPM mutation was found, and NPM mutations in MDS patients were demonstrated for the first time. The results provides new hints for NPM gene mutations in the pathogenesis of AML and MDS.
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi 08/2006; 27(7):470-3.
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ABSTRACT: Balanced chromosomal translocations rarely occur in myelodysplastic syndromes (MDS). We describe here in three further Chinese patients with myelodysplastic syndromes (MDS) whose cytogenetic analysis showed t(1;3)(p36;q21). We detected the expression pattern of MEL1 and MEL1s in BM of two healthy subjects and the three patients, and found that the expression of MEL1s was overexpressed in MDS patients with t(1;3)(p36;q21). Our findings combined previous observations reported in literature support that MDS patients with t(1;3)(p36;q21) should be a new specific subset of MDS. Imbalance of a complete MEL1 message with a PR domain and a short MEL1 message lacking a PR domain (MEL1S) might be involved in the pathogenesis of these patients.
Leukemia Research 04/2006; 30(3):332-4. · 2.92 Impact Factor
