MDM2 promoter SNP309 is associated with an increased susceptibility to chronic lymphocytic leukemia and correlates with MDM2 mRNA expression in Chinese patients with CLL

2011 ◽  
Vol 130 (9) ◽  
pp. 2054-2061 ◽  
Author(s):  
Hua-Jie Dong ◽  
Cheng Fang ◽  
Lei Fan ◽  
Dan-Xia Zhu ◽  
Dong-Mei Wang ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mrna Expression ◽  
Lymphocytic Leukemia ◽  
Chinese Patients ◽  
Mdm2 Mrna ◽  
Increased Susceptibility

MDM2 Promoter SNP309 Is Associated with An Increased Susceptibility to Chronic Lymphocytic Leukemia and Correlates with MDM2 mRNA Expression In Chinese Population

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2424-2424
Author(s):  
Hua-Jie Dong ◽  
Cheng Fang ◽  
Lei Fan ◽  
Dan-Xia Zhu ◽  
Dong-Mei Wang ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mrna Expression ◽  
Lymphocytic Leukemia ◽  
Mdm2 Snp309 ◽  
Wild Type ◽  
Chinese Populations ◽  
Increased Risk ◽  
Mdm2 Expression ◽  
Mdm2 Mrna

Abstract Abstract 2424 Objective: A single nucleotide polymorphism (SNP) at position 309 in the promoter region of MDM2 leading to increased expression of MDM2 and attenuated function of p53 has recently been suggested as an unfavorable prognostic marker in chronic lymphocytic leukemia (CLL) although this has been questioned. Because inactivation of p53 by deletion and/or mutations also impacts on the clinical course of CLL, we assessed the role of the SNP309 genotype in CLL among Chinese populations. Methods: The MDM2 SNP309 genotypes in 166 CLL patients and 260 healthy controls were detected by the PCR-RFLP method, which all CLL samples was confirmed by direct DNA sequencing. We correlated the results with established CLL prognostic factors, overall survival (OS) and treatment-free survival (TFS). In addition, the correlation of the MDM2 SNP309 genotype with the MDM2 mRNA expression level was evaluated by QPCR. Results: 1. The MDM2 T309G genotype frequencies were 22.9% (T/T), 48.2% (T/G), and 28.9% (G/G) among the cases, and 31.5% (T/T), 54.2% (T/G), and 14.2% (G/G) in the control subjects, and the difference was statistically significant (P=0.001). Logistic regression analyses revealed that the SNP309 G/G genotype instead of T/G heterozygote was associated with a significantly increased risk of CLL (adjusted OR = 2.8; 95% CI 1.57–4.98; P <0.001 for 309 G/G and adjusted OR = 1.22; 95% CI 0.76–1.96; P= 0.401 for 309 T/G, respectively), compared with the SNP309 T/T genotype. Age at onset of CLL was similar irrespective of MDM2 status. The median age at diagnosis for the different genotypes was 65 years for T/T and 62 years for T/G, 63 years for G/G (P>0.05). 2. In the entire cohort, no correlation was shown between the MDM2 SNP309 genotypes and Binet stage, IGHV mutational status, p53 mutation/deletion and no association existed between any particular MDM2 SNP309 genotype, OS and TFS. 3. The frequency of MDM2 mRNA expression in GG genotype was significantly higher than that in T/G (P=0.026) and T/T genotypes (P=0.003). Furthermore, patients with p53 aberrations (mutated and deleted) MDM2 expression were higher than SNP 309 T/G (P=0.046) and T/T genotypes (P=0.001), but were similar with G/G genotype with p53 wild-type (P=0.532), which prompted us to study the role of the polymorphism in p53 wild-type individuals. 4. In the p53 wild-type groups, we also confirmed MDM2 expression levels with SNP 309 G/G (P<0.001) and T/G (P=0.009) genotypes were higher than T/T genotypes. Moreover, survival analysis showed that the patients with SNP309 G/G (mean, 27.5 months; 95% CI, 21.2–33.9 months, P= 0.021) and T/G genotypes (mean, 48.7 months; 95% CI, 36.5–61.3 months, P= 0.045) both had significantly shorter TFS than SNP309 T/T genotype (mean, 97.2 months; 95% CI, 62.5–131.8 months). Conclusions: The results suggest that MDM2 309G polymorphisms contribute to the risk of developing CLL. The unfavorable SNP309 G/G genotype was associated with a gene-dosage-dependent increase of MDM2 expression. MDM2 SNP309 was found to be associated with TFS in p53 wild-type Chinese populations. Disclosures: No relevant conflicts of interest to declare.

High CD49d protein and mRNA expression predicts poor outcome in chronic lymphocytic leukemia

2009 ◽  
Vol 131 (3) ◽  
pp. 472-480 ◽  
Author(s):  
Holger Nückel ◽  
Magdalena Switala ◽  
Crista H. Collins ◽  
Ludger Sellmann ◽  
Hans Grosse-Wilde ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mrna Expression ◽  
Lymphocytic Leukemia ◽  
Poor Outcome

Prognostic Significance of Molecular Cytogenetics in Chinese Patients with Chronic Lymphocytic Leukemia: A Prospective Unicentric Analysis.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4690-4690
Author(s):  
Wei Xu ◽  
Jianyong Li ◽  
Li Li ◽  
Yujie Wu ◽  
Hui Yu ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Survival Time ◽  
Gene Deletion ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Chinese Patients ◽  
Molecular Cytogenetic ◽  
Western Countries ◽  
Cytogenetic Aberrations ◽  
Atm Gene

Abstract B-cell chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia in the Western countries, however, infrequent in the Eastern. It is characterized by a highly variable clinical course; some patients survive more than 20 years, whereas others die within a few months of diagnosis. The characteristics of Chinese patients with CLL compared with the Western countries have not yet been clarified. The aim of this study was to prospectively explore characteristics and prognostic significance of molecular cytogenetic aberrations in Chinese patients with CLL. Interphase fluorescence in situ hybridization (FISH) and a panel of probes (LSI D13S319,LSI p53,LSI ATM,CEP 12,LSI MYB,LSI IGHC/IGHV) were used to detect cytogenetics abnormalities in 95 patients with CLL. Cytogenetics aberrations and their association with some other prognostic factors were analyzed. Kaplan-Meier was used for survival time. Out of the 95 CLL patients, molecular cytogenetic aberrations were found in 69 (72.6%) cases and 25 (26.3%) patients showed more than two kinds of abnormalities. The most frequent abnormalities detected were del(13q14) in 46 cases (48.4%), followed by trisomy of chromosome 12 in 22 patients (23.2%), 14q32 rearrangement in 21 patients (22.1%), del(17p13) in 16 patients (16.8%), del(11q22) in 9 patients (9.5%) and del(6q23) in 5 patients (5.3%). There were no significant differences of molecular cytogenetic aberrations in sex, age, Binet stages, peripheral lymphocyte count, and the levels of lactate dehydrogenase (LDH), β2-microglobulin (β2-MG), and ZAP-70. The TP53 and ATM gene deletion rates were higher in the group of CD38 high expression than that in the group of low expression (P=0.047 and P=0.001). No patient with TP53 and ATM gene deletion achieved complete response (CR) among 41 patients received treatment with fludarabine. The survival time was shorter in patients with high levels of LDH (P=0.028), β2-MG (P=0.012), and CD38 (P=0.000), and with TP53 gene deletion (P=0.000). Patients with sole del(13q14) had longer survival time than those with other abnormalities (P=0.044). It was showed that panel FISH has greatly increased the sensitivity of cytogenetic analyses and del(13q14) was the most frequent abnormality in CLL. Detection of molecular cytogenetic aberrations with FISH had important prognostic significance in CLL. The patients with sole del(13q14) had favorable outcome, and with del(17p13) had poor outcome.

Distinctive IgVH Gene Segments Usage and Mutation Status in Chinese Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4708-4708
Author(s):  
Lijuan Chen ◽  
Yaping Zhang ◽  
Wenjuuan Zheng ◽  
Jianyong Li ◽  
Changgeng Ruan
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Gene Family ◽  
Gene Families ◽  
Lymphocytic Leukemia ◽  
Chinese Patients ◽  
Chain Gene ◽  
Mutation Status ◽  
Significant Difference ◽  
Variable Heavy ◽  
Vh Gene

Abstract Chronic lymphocytic leukemia (CLL) is characterized by the relentless accumulation of monoclonal B cells with the appearance of small mature lymphocytes and a characteristic CD5 and CD19 co-expression immunophenotype. The incidence of CLL in Asian countries is lower than that in the Western ones, where CLL is the most common leukemia. To evaluate the frequency and mutation status of immunoglobulin (Ig) variable heavy chain gene (IgVH) expression in Chinese patients with CLL. We investigated IgVH gene segments usage and mutation status by multiplex RT-PCR in 52 CLL patients, and analyzed the relationship between IgVH somatic mutation status and the expression of CD38, ZAP-70 and CLLU1. 38 patients had mutated IgVH, and 14 had unmutated IgVH. The most frequently expressed VH gene family was found to be VH3 (46.2%) followed by VH4 (40.4%), VH1 (5.8%), VH2 (5.8%) and VH7 (1.9%), with no expression of VH5 and VH6 gene families. VH1-69 and VH3-21 which commonly overused in Western CLL weren’t detected in our cohort. The frequency of IgVH gene families indicates significant difference in Chinese CLL patients compared with Western patients, suggesting involvement of ethnic and/or environmental factors in CLL disease initiation. IgVH gene mutation status was significantly associated with the expression of CD38 and CLLU1. The expression of them may be simple and reliable surrogates for the identification of IgVH mutations. VH gene family usage and mutation status VH family n Mutated VH gene Unmutated VH gene VH1 3 3 0 VH2 3 2 1 VH3 24 19 5 VH4 21 16 5 VH5 0 0 0 VH6 0 0 0 VH7 1 0 1

The Prognostic Significance of Positive Direct Antiglobulin Test in Chinese Patients with Chronic Lymphocytic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4183-4183
Author(s):  
Wei Xu ◽  
Jianyong Li ◽  
Xin Cao ◽  
DAN-Xia Zhu ◽  
Lin Yao ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Prognostic Significance ◽  
Prognostic Indicator ◽  
Lymphocytic Leukemia ◽  
Direct Antiglobulin Test ◽  
Chinese Patients ◽  
Prognostic Impact ◽  
Antiglobulin Test ◽  
Positive Direct

Abstract Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemias in the Western countries, however, infrequent in the Eastern. Autoimmune hemolytic anemia (AHA) is a complication in chronic lymphocytic leukemia (CLL). The direct antiglobulin test (DAT) may be positive at some time during the disease course in up to 35% of cases, but overt AHA occurs less frequently. The aim of the study was to explore the prognostic impact of positive DAT in Chinese patients with CLL and its correlation with other prognostic factors, including Binet stages, lymphocyte count in peripheral blood, lactate dehydrogenase (LDH), β2-microglobulin (β2-MG), IgVH mutation status, ZAP-70, CD38 and cytogenetic abnormalities. Out of the 80 Chinese patients with CLL, positive DAT was found in 21 (30.6%) cases. The incidence of positive was 12.5% in Binet A, 23.8% and 44.4% in Binet B and C, respectively. The incidence of positive DAT was significantly increased at Binet C, compared with Binet A (P=0.006), and the presence of higher LDH and β2-MG levels correlated strongly with positive DAT (P=0.006 and P=0.004, respectively). Patients with unmutated IgVH genes had higher incidence of positive DAT than did patients with IgVH mutations (P=0.042), and positive DAT was also associated with higher level of ZAP-70 and CD38 (P=0.004 and P&lt;0.001, respectively). We also analyzed positive DAT in different cytogenetic subgroups. Higher incidence of positive DAT was found in patients with unfavorable cytogenetic aberrations (deletion in 17p13 or 11q22) in contrast to lower level in good risk cytogenetics (deletion in 13q as the sole abnormality) (P = 0.002). Positive DAT was associated with poor outcome. Survival analysis showed that the patients with positive DAT had significantly shorter OS (mean, 106.3 months) (95% CI, 74.7 to 137.8 months) than the patients negative DAT (mean, 151.5 months) (95% CI, 122.3 to 180.6 months) (P=0.024). Patients treated with fludarabine were not likely to remain DAT positive and to change from negative to positive (P=0.209). In conclusion, DAT status provides a new prognostic indicator and correlates with other clinical or laboratory prognostic factors, and might be applied for the assessment of prognosis in patients with CLL.

Prognostic Factors of Chinese Patients with Chronic Lymphocytic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4387-4387
Author(s):  
Jianyong Li ◽  
Wei Xu ◽  
Chun Qiao ◽  
Yu-Jie Wu ◽  
Kourong Miao ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Chronic Lymphocytic Leukemia ◽  
Gene Families ◽  
Lymphocytic Leukemia ◽  
High Expression ◽  
Chinese Patients ◽  
Cytogenetic Abnormalities ◽  
Western Countries ◽  
Mutational Status ◽  
Clinical Stages

Abstract Abstract 4387 Chronic lymphocytic leukemia (CLL) is one of the most common lymphoid malignancies in the Western countries, however, infrequent in Asian populations. Although the median survival is around 10 years, CLL is a disease with an extremely variable clinical course with overall survival times ranging from months to decades; some patients never need treatment, while others require intensive treatment early after diagnosis. Some factors, such as clinical stages, IGHV mutational status, cytogenetic abnormalities, ZAP-70, and the expression of CD38 in leukaemic cells, were strong indicator of prognosis in CLL. However, the prognostic factors of Chinese patients with CLL compared with the Western countries have not yet been clarified. The aim of this study was to explore the influence of factors on the prognosis of Chinese patients with CLL. One hundred and twenty-nine patients with CLL were enrolled in this study. Multiplex PCR and sequencing, fluorescence in situ hybridization (FISH), and flow cytometry were used to detect IGHV mutational status, cytogenetic abnormalities, and the expression of ZAP-70 and CD38, respectively. A panel of FISH probes included 13q14 (D13S319), 17p13 (p53 gene), 11q23 (ATM gene), 6q23(MYB gene), the centromere of chromosome 12 (D12Z3) and 14q32 (IGHC/IGHV). In 129 CLL patients, according to the Binet clinical staging system, 65 (50.4 %) patients were in Binet A, 28 (21.7 %) in Binet B and 36 (27.9 %) in Binet C. Eighty-four (65.1%) patients had mutated IGHV, and 45 (34.9%) had unmutated IGHV. The most frequently expressed VH gene family was found to be VH3 (50.4%) followed by VH4 (32.6%), VH1 (10.9%), VH2 (2.3%), VH5(2.3%) and VH7 (1.6%), with no expression of VH6 gene families. VH1-69 and VH3-21 which commonly overused in Western CLL patients were very low in our cohort (0.8% and 3.1%, respectively). Molecular cytogenetic aberrations were found in 94 patients (72.9%) and 36 patients (27.9%) with more than two abnormalities. The most frequent abnormalities detected in our patients was del(13q14), with an incidence of 53.0%, followed by 14q32 translocation of 20.2%, +12 of 18.3%, del(11q23) of 10.8%, del(17p13) of 10.o%, and del(6q23) of 6.1%. Forty-one patients (31.8%) were positive for ZAP-70 (≥20%), and 51 patients (39.5%) were positive for CD38 (≥30%). With a median follow-up of 32 months (range, 4-58 months), eight patients (6.2%) died (CLL-related deaths). In univariate analysis for survival, advanced Binet stage (P=0.023), unmutated IGHV status (P=0.002), deletions of 17p13 or 11q23 (P=0.003), high expression of ZAP-70 (P=0.034), and high expression of CD38 (P=0.046) were poor prognostic factors. The prognostic factors with statistical significance were further used in a two-variables Cox analysis, which comparing unmutated IGHV status to other prognostic factors individually to show prognostic independence. The unmutated IGHV status were the independent prognostic factors and strongly associated with OS. This study demonstrates that the frequencies of IGHV gene families indicated significant difference in Chinese CLL patients compared with Western patients, suggesting involvement of ethnic and/or environmental factors in CLL disease initiation. The unmutated IGHV status, Binet clinical stages, Chromosomal aberrations of del(17p13) and del(11q23), high expression of ZAP-70 and CD38 have been shown highly predictive prognostic value for Chinese patients with CLL. Disclosures: No relevant conflicts of interest to declare.

Trisomy 8 in two newly diagnosed Chinese patients with chronic lymphocytic leukemia

2009 ◽  
Vol 192 (2) ◽  
pp. 79-81 ◽  
Author(s):  
Wei Xu ◽  
Xin Cao ◽  
Qiong Liu ◽  
Lei Fan ◽  
Kou-Rong Miao ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Lymphocytic Leukemia ◽  
Chinese Patients ◽  
Newly Diagnosed ◽  
Trisomy 8

scholarly journals Low MCL-1 mRNA expression correlates with prolonged survival in B-cell chronic lymphocytic leukemia

Leukemia ◽  
2007 ◽  
Vol 22 (6) ◽  
pp. 1291-1293 ◽  
Author(s):  
L Véronèse ◽  
O Tournilhac ◽  
P Verrelle ◽  
F Davi ◽  
G Dighiero ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Mrna Expression ◽  
Lymphocytic Leukemia ◽  
Prolonged Survival ◽  
Cell Chronic Lymphocytic Leukemia

scholarly journals Analysis of CD38 and ZAP70 mRNA expression among cytogenetic subgroups of Iranian chronic-lymphocytic-leukemia patients

2011 ◽  
Vol 10 (4) ◽  
pp. 2415-2423 ◽  
Author(s):  
H. Teimori ◽  
M.T. Akbari ◽  
M. Hamid ◽  
M. Forouzandeh ◽  
E. Bibordi
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Mrna Expression ◽  
Lymphocytic Leukemia
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