Methylenetetrahydrofolate reductase (MTHFR) gene 677C>T and 1298A>C polymorphisms are associated with differential apoptosis of leukemic B cells in vitro and disease progression in chronic lymphocytic leukemia (original) (raw)
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Blood, 2008
Leukemia-cell expression of ZAP-70, CD38, or unmutated immunoglobulin heavy chain variable region genes (U-IGHV) each is associated with aggressive disease in patients with chronic lymphocytic leukemia (CLL). To assess the relative strength of each marker, we defined thresholds for designating a case as positive for CD38 or ZAP-70 in a test cohort of 307 patients and used these data-defined criteria to stratify patients in an independent cohort of 705 patients. Multivariable analysis revealed that ZAP-70 was the strongest risk factor. Knowledge of the IGHV mutation status or CD38 did not improve our ability to predict the time to first treatment except for ZAP-70negative cases, which could be segregated into 2 groups of intermediate-risk or low-risk disease based on whether they expressed unmutated or mutated IGHV. ZAP-70 maintained its high relative prognostic value for the subset of patients with early-stage, asymptomatic disease , including patients evaluated within 1 year of diagnosis. Although it is premature to recommend therapy based on these risk factors, patients with ZAP-70positive CLL cells should be monitored closely for disease progression as they have a median time from diagnosis to requiring initial therapy by standard criteria of approximately 3 years. (Blood. 2008; 112:1923-1930) samples collected from a test cohort of 307 patients with CLL who previously were characterized for expression of ZAP-70 and IGHV. 22 Using data-defined criteria for designating a sample positive for CD38 or ZAP-70, we assessed the relative value of CD38 or ZAP-70, or use of U-IGHV in predicting the time to initial treatment of patients in an independent validation cohort of 705 CLL patients followed by the CLL Research Consortium (CRC). Methods Patients samples and cell processing Blood was obtained from CLL patients enrolled in the CRC upon written informed consent. Blood mononuclear cells were prepared using Ficoll-Hypaque 1077 (Sigma-Aldrich, St Louis, MO) and suspended in fetal-calf serum containing 10% dimethylsulfoxide for storage in liquid nitrogen. 22 The institutional review board of UCSD has reviewed and approved this study in accordance with the requirements of the Code of Federal Regulations on the Protection of Human Subjects and the Declaration of Helsinki. Patient characteristics The test cohort was composed of 307 CLL patients (201 males [65%] and 106 females [35%]) who had a median age at diagnosis of 52 years (range, 30-77 years). The validation cohort was composed of 705 CLL patients
Leukemia, 2005
Prognostic predictions in B-cell chronic lymphocytic leukemia (B-CLL) at early clinical stage are based on biological disease parameters, such as ZAP-70 and CD38 protein levels, genomic aberrations as well as immunoglobulin variable heavy chain gene (IgV H ) mutation status. In the current study, ZAP-70 and CD38 expressions were examined by flow cytometry in 252 patients with B-CLL. Cytoplasmic ZAP-70 expression in more than 20% (ZAP-70 þ ) and surface CD38 expression on more than 30% (CD38 þ ) of B-CLL cells were associated with an unfavorable clinical course. The levels of ZAP-70 and CD38 did not change over time in the majority of patients where sequential samples were available for analysis. Combined analysis of ZAP-70 and CD38 yielded discordant results in 73 patients (29.0%), whereas 120 patients (47.6%) were concordantly negative and 59 patients (23.4%) were concordantly positive for ZAP-70 and CD38 expression. Median treatment-free survival times in patients whose leukemic cells were ZAP-70 þ CD38 þ was 30 months as compared to 130 months in patients with a ZAP-70 À CD38 À status. In patients with discordant ZAP-70/CD38 results, the median treatment-free survival time was 43 months. Thus, ZAP-70 and CD38 expression analyses provided complementary prognostic information identifying three patient subgroups with good, intermediate and poor prognosis. Over-representation of high-risk genomic aberrations such as 17p deletion or 11q deletion and distribution of the IgV H mutation status in B-CLL discordant for ZAP-70/ CD38 pointed toward a distinct biologic background of the observed disease subgroups. This finding was also supported by microarray-based gene expression profiling in a subset of 35 patients. The expression of 37 genes differed significantly between the three groups defined by their expression of ZAP-70 and CD38, including genes that are involved in regulation of cell survival and chemotherapy resistance.
Blood, 2009
4388 Introduction Chronic lymphocytic leukemia (CLL) is a heterogeneous disease; ZAP-70 protein expression and IgVH mutational status have shown to be strong associated and to offer important prognostic information. Aim Our aim was to determine gene expression profiles of 46 CLL patients divided into three classes: group one (n=26) with mutated IgVH and ZAP-70-, group two (n=12) with unmutated IgVH and ZAP-70+, and group three (n=8) included CLL patients with unmutated IgVH and ZAP-70-, or mutated IgVH and ZAP-70+ respectively. Afterwards, in a second phase of the study, 16 other patients were investigated. Finally, the purpose was to define prognostic biomarkers and the biological pathways related to CLL. Patients and Methods We determined gene expression profiles using Affymetrix HG U133 Plus 2.0 in CD19+ leukemic cells. Differentially expressed genes were detected using ANOVA and t-test adapted for microarray data analysis and corrected for multiple testing using false discovery ...
Clinical and molecular predictors of disease severity and survival in chronic lymphocytic leukemia
American Journal of Hematology, 2007
Several parameters may predict disease severity and overall survival in chronic lymphocytic leukemia (CLL). The purpose of our study of 190 CLL patients was to compare immunoglobulin heavy chain variable region (IgV H ) mutation status, cytogenetic abnormalities, and leukemia cell CD38 and Zap-70 to older, traditional parameters. We also wanted to construct a simple, inexpensive prognosis score that would significantly predict TTT and survival in patients at the time of diagnosis and help practicing clinicians. In univariate analyses, patients with higher clinical stage, higher leukocyte count at diagnosis, shorter leukocyte doubling time, elevated serum lactate dehydrogenase (LDH), unmutated immunoglobulin heavy chain variable region (IgV H ) genes, and higher CD38 had a shorter overall survival and time-to-treatment (TTT). CLL cell Zap-70 expression was higher in patients with unmutated IgV H , and those with higher Zap-70 tended to have shorter survival. IgV H 4-34 or IgV H 1-69 was the most common IgV H genes used (16 and 12%, respectively). Of those with IgV H 1-69, 86% had unmutated IgV H and had a significantly shorter TTT. A cytogenetic abnormality was noted in 71% of the patients tested. Patients with 11q22 del and 17p13 del or complex abnormalities were significantly more likely to have unmutated IgV H . We found that a prognostic score constructed using modified Rai stage, cellular CD38, and serum LDH (parameters easily obtained clinically) significantly predicted TTT and survival in patients at the time of diagnosis and performed as well or better than models using the newer markers. Am.
Molecular basis of chronic lymphocytic leukemia diagnosis and prognosis
Cellular Oncology, 2015
Backgrounds Chronic lymphocytic leukemia (CLL) is the most common type of leukemia in adults and is characterized by a clonal accumulation of mature apoptosis-resistant neoplastic cells. It is also a heterogeneous disease with a variable clinical outcome. Here, we present a review of currently known (epi)genetic alterations that are related to the etiology, progression and chemo-refractoriness of CLL. Relevant literature was identified through a PubMed search of English-language papers using the terms CLL, signaling pathway, cytogenetic abnormality, somatic mutation, epigenetic alteration and micro-RNA. Results CLL is characterized by the presence of gross chromosomal abnormalities, epigenetic alterations, micro-RNA expression alterations, immunoglobulin heavy chain gene mutations and other genetic lesions. The expression of unmutated immunoglobulin heavy chain variable region (IGHV) genes, ZAP-70 and CD38 proteins, the occurrence of chromosomal abnormalities such as 17p and 11q deletions and mutations of the NOTCH1, SF3B1 and BIRC3 genes have been associated with a poor prognosis. In addition, mutations in tumor suppressor genes, such as TP53 and ATM, have been associated with refractoriness to conventional chemotherapeutic agents. Micro-RNA expression alterations and aberrant methylation patterns in genes that are specifically deregulated in CLL, including the BCL-2, TCL1 and ZAP-70 genes, have also been encountered and linked to distinct clinical parameters. Conclusions Specific chromosomal abnormalities and gene mutations may serve as diagnostic and prognostic indicators for disease progression and survival. The identification of these anomalies by state-of-the-art molecular (cyto)genetic techniques such as fluorescence in situ hybridization (FISH), comparative genomic hybridization (CGH), single nucleotide polymorphism (SNP) microarray-based genomic profiling and next-generation sequencing (NGS) can be of paramount help for the clinical management of these patients, including optimal treatment design. The efficacy of novel therapeutics should to be tested according to the presence of these molecular lesions in CLL patients.
Frequency of Zap-70 and CD38 in Newly Diagnosed Cases of B-Cell Chronic Lymphocytic Leukemia
Research Article, 2019
Amongst all chronic lymphoproliferative disorders B-CLL is the most common. Clinical behavior of CLL is very variable and in order to identify the clinical spectrum there is a need for risk adaptive prognostic markers which will further facilitate in management strategy. Currently available molecular biomarkers ZAP-70 & CD-38 have gain much interest in providing useful prognostic information in patients diagnosed as B-CLL.
Prognostic significance of combined analysis of ZAP70 and CD38 in chronic lymphocytic leukemia
American Journal of Hematology, 2007
The clinical heterogeneity that characterizes chronic lymphocytic leukemia (CLL) poses critical questions concerning the identification of high risk patients. Unmutated IgV H genes, CD38 and ZAP-70 expression have emerged as the most useful tools in identifying aggressive CLL. The simultaneous expression of ZAP-70 and CD38 in 157 patients with CLL has been evaluated. Fifty-seven patients (36%) were positive for ZAP-70 and 46 patients (29%) were positive for CD38. Both molecules were highly correlated and predictive of the clinical course of the disease. According to the simultaneous evaluation of ZAP-70 and CD38, patients were divided into three groups. In 81 patients (52%), there was a negative concordance of both molecules (ZAP-70 À /CD38 -); in 27 patients (17%) there was a positive concordance (ZAP-70 1 /CD38 1 ); in 49 patients (31%) there was a discordant expression (ZAP-70 1 /CD38and ZAP-70 -/CD38 1 ). A comparison of the clinical and laboratory data showed in ZAP-70 1 /CD38 1 patients a significantly higher bone marrow and peripheral blood lymphocytosis, lower hemoglobin levels, more advanced clinical stage, and higher number of unmutated IgV H status with respect to the other two groups. Furthermore, ZAP-70 1 /CD38 1 patients displayed a much shorter treatment-free interval (median 12 months vs 42 months in discordant patients and not reached in ZAP-70 -CD38patients). These results prove that the concomitant evaluation of ZAP-70 and CD38 expression allows the separation of CLL patients in prognostic subgroups and suggest that their simultaneous assessment should become an integral component of the CLL diagnostic grid. Am. J. Hematol. 82:787-791, 2007. V V C 2007 Wiley-Liss, Inc.