Progressive disease in chronic lymphocytic leukemia is correlated with the DNA methylation index

2007 ◽  
Vol 31 (6) ◽  
pp. 773-777 ◽  
Author(s):  
Margaret K. Yu ◽  
Hector Bergonia ◽  
Aniko Szabo ◽  
John D. Phillips
Keyword(s):  
Dna Methylation ◽  
Chronic Lymphocytic Leukemia ◽  
Progressive Disease ◽  
Lymphocytic Leukemia ◽  
Methylation Index

Global DNA Hypermethylation in Chronic Lymphocytic Leukemia Correlates with Progressive Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5006-5006
Author(s):  
Margaret K. Yu ◽  
Aniko Szabo ◽  
Hector Bergonia ◽  
Anna Senina ◽  
John D. Phillips
Keyword(s):  
Dna Methylation ◽  
Chronic Lymphocytic Leukemia ◽  
Progressive Disease ◽  
Lymphocytic Leukemia ◽  
Global Dna Methylation ◽  
Dna Hypomethylation ◽  
Physician Visits ◽  
Mutational Status ◽  
Trisomy 12 ◽  
One Year

Abstract Global DNA hypomethylation is observed in chronic lymphocytic leukemia, but methylation has not been correlated with clinical outcome. Although patient survival correlates with factors such as the mutational status of the immunoglobulin variable genes, karyotype abnormalities, Zap-70, and CD38 expression, none of these predictors have altered the way clinicians practice. We report interim results in the assessment of global DNA methylation as a predictor of aggressive disease in patients with chronic lymphocytic leukemia. Fourteen patients with chronic lymphocytic leukemia donated blood samples for DNA studies at the same time as blooddraws for their physician visits. All the treatments occurred within one year and the follow-ups were at least within 12 months except for one patient. We thus classified patients into two groups: those who required treatment within one year and those who did not. The cutoff in methylation level providing the smallest observed prediction error was 4.125%; it correctly predicted 5/6 patients not needing treatment within a year and 5/6 patients needing treatment. These observed classification rates were adjusted for the bias resulting from the optimal selection of the cutoff using bootstrap. The adjusted sensitivity and specificity were 74% and 80%, respectively. Asymptomatic patients with chronic lymphocytic leukemia tended to have lower levels of global DNA methylation (median 3.5%) compared to symptomatic patients (median 4.5%). In other words, high levels of global DNA methylation were associated with higher disease burden, corresponding with higher lymphocyte and white blood cell numbers. Five patients without immediate need for cytoreductive therapy were enrolled on a pilot treatment trial with low-dose cladribine, by subcutaneous injection. Three out of the five patients have had a clinical response, a secondary endpoint. Two of the patients have achieved a partial response, as defined by the NCI sponsored working group, with at least a three month follow-up after discontinuation of the drug. Of the two patients with stable or progressive disease on cladribine, their global DNA methylation levels were higher, correlating with more chemotherapy resistant disease. DNA methylation Levels in Patients with Chronic Lymphocytic Leukemia Age Sex %5-MedC Zap-70 CD-38 Rai Stage FISH Req Treatment (mos) FISH= fluorescence in situ hybridization; Zap-70 assessed by immunochemistry 51 M 5.045 positive positive 4 Del13q14 0.75 73 F 4.865 positive not assessed 4 not assessed 12+ 52 F 4.665 positive negative 2 Del13q14 2 57 M 4.62 negative negative 4 Del13q14 2 66 M 4.59 positive not assessed 4 Del13q14 (5/05) and Del 17p and Del 13q14 (7/05) 0.25 67 M 4.14 positive positive 4 Trisomy 12 10 47 M 4.055 negative negative 0 not assessed 12+ 59 M 3.9 negative negative 2 46XY 0 72 M 3.54 negative not assessed 0 not assessed 8+ 64 M 3.55 positive not assessed 1 Del13q14 12+ 70 F 3.47 not assessed negative 4 Trisomy 12 12+ 68 F 3.47 positive negative 2 not assessed 12+ 77 M 3.2 not assessed not assessed 0 not assessed 12+ DNA Methylation Levels in patients with Chronic Lymphocytic Leukemia DNA Methylation Levels in patients with Chronic Lymphocytic Leukemia

Composite Prolymphocytoid and Hodgkin Transformation of Chronic Lymphocytic Leukemia

2000 ◽  
Vol 124 (6) ◽  
pp. 907-909 ◽  
Author(s):  
Maureen J. O'Sullivan ◽  
Zahid Kaleem ◽  
Michael J. Bolger ◽  
Paul E. Swanson ◽  
Mary M. Zutter
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Hodgkin Lymphoma ◽  
Progressive Disease ◽  
Plasma Cells ◽  
Single Agent ◽  
Malignant Neoplasm ◽  
Lymphocytic Leukemia ◽  
Richter Syndrome ◽  
Classic Hodgkin Lymphoma ◽  
Single Agent Chemotherapy

Abstract The indolent course of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is occasionally altered by transformation to a histologically distinct, rapidly progressive, and clinically unresponsive hematologic malignant neoplasm. We report a case of CLL that, after 3 years of slowly progressive disease and treatment with single-agent chemotherapy (fludarabine phosphate), underwent a composite prolymphocytoid and classic Hodgkin lymphoma transformation. The diagnosis of classic Hodgkin lymphoma was based on the presence of Reed-Sternberg cells with typical morphologic structure and immunophenotype (CD15+, CD30+, CD45−, CD20−) associated with the characteristic polymorphous inflammatory background consisting of numerous eosinophils, plasma cells, and reactive T lymphocytes. The remainder of the lymph node and the peripheral blood showed increased numbers of prolymphocytes admixed with typical small CLL cells. Recognition of such a transformation is of the utmost importance, since histologically similar Reed-Sternberg–like cells may be seen in Richter transformation. In contrast to prolymphocytoid transformation of CLL, Richter syndrome is rapidly fatal, with a median survival of 4 to 5 months. The patient pursued a clinical course similar to pure prolymphocytoid transformation and died with disease after 30 months following treatment with combination chemotherapy.

scholarly journals Sex-related DNA methylation differences in B cell chronic lymphocytic leukemia

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Shuchun Lin ◽  
Yun Liu ◽  
Lynn R. Goldin ◽  
Chen Lyu ◽  
Xiangyin Kong ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Cell Chronic Lymphocytic Leukemia

No evidence for DNA methylation of theATMpromoter CpG island in chronic lymphocytic leukemia

2012 ◽  
Vol 53 (7) ◽  
pp. 1420-1422 ◽  
Author(s):  
Thomas Mikeska ◽  
Dennis A. Carney ◽  
John F. Seymour ◽  
Alexander Dobrovic
Keyword(s):  
Dna Methylation ◽  
Chronic Lymphocytic Leukemia ◽  
Cpg Island ◽  
Lymphocytic Leukemia

Methylation Profile of B-Chronic Lymphocytic Leukemia Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2951-2951
Author(s):  
Jun Fan ◽  
Asou Norio ◽  
Masao Matsuoka
Keyword(s):  
Dna Methylation ◽  
Chronic Lymphocytic Leukemia ◽  
Cell Lines ◽  
Mammalian Cells ◽  
Mononuclear Cells ◽  
Cpg Island ◽  
Methylation Status ◽  
Lymphocytic Leukemia ◽  
Dna Hypomethylation ◽  
Peripheral Blood Mononuclear

Abstract DNA methylation plays an important role in the development and aging of mammalian cells, and its dysregulation has been frequently observed in cancer cells. The purpose of this study is to investigate the involvement of aberrant DNA methylation in B chronic lymphocytic leukemia (B-CLL) cells. We compared methylation status of B-CLL cells isolated from patients with that of normal CD19+ cells isolated from health donors by methylated CpG island amplification/representative difference analysis method. 5 hypermethylated and 27 hypomethylated DNA regions were identified in B-CLL sample. Among the 27 hypomethylated regions, 5 located on chromosome 9q34, 3 on 10q25-26 and 4 on 19q13. Methylation status was confirmed by sequencing using sodium bisulfite-treated DNA samples. By comparing DNA samples from same patients at different clinical stages, we found that lower methylation density in these regions is linked with disease progression. Expression of 15 genes surrounding hypomethylated regions was studied by RT-PCR. Expression of laminin beta3 gene and melanotransferrin gene was found to be upregulated in all B-CLL cell lines as well as lymphoma cell lines comparing with normal CD19+ peripheral blood mononuclear cells. B-cell CLL/lymphoma 11b gene showed increased expression in only 2 B-CLL cell lines. For other genes, no transcriptional change was found regardless of changed DNA methylation. This study showed the predominance of DNA hypomethylation in B-CLL cells compared with hypermethylation. Hypomethylated regions clustered in a limited number of chromosomes and methylation density appeared to be inversely correlated with disease progress. Figure Figure

ZAP-70 Is Not Phosphorylated on the Activating Tyrosine Residue (Tyr319) in Chronic Lymphocytic Leukemia and B-Cell Lymphoma Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 178-178
Author(s):  
Stefania Gobessi ◽  
Aleksandar Petlickovski ◽  
Luca Laurenti ◽  
Dimitar G. Efremov
Keyword(s):  
T Cells ◽  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Progressive Disease ◽  
Cell Receptor ◽  
Kinase Domain ◽  
Lymphocytic Leukemia ◽  
Bcr Signaling ◽  
Cell Receptor Signaling

Abstract The protein tyrosine kinase ZAP-70 is expressed at high levels in leukemic B-cells from chronic lymphocytic leukemia (CLL) patients with progressive disease and short survival. ZAP-70 is a key component of the proximal T-cell receptor signaling pathway and is highly homologous to Syk, an important B-cell receptor signaling (BCR) molecule. Recent studies indicate that ZAP-70 may participate in BCR signaling as well, but the mechanism of action is still not well understood. In T-cells, upon TCR stimulation ZAP-70 becomes phosphorylated on Tyr319 by the Src-like kinase Lck, which results in the release of the ZAP-70 kinase domain from an autoinhibited state to a fully active conformation. The Tyr319 site in ZAP-70 corresponds to the Tyr352 site in Syk, which is phosphorylated in B-cells following BCR stimulation. We therefore investigated the activation status of ZAP-70 and Syk in BCR stimulated CLL B-cells, using phosphorylation of Tyr319 and Tyr352 as markers of their activation. Analysis of 10 ZAP-70-positive CLL samples by immunoblotting with the phospho-ZAP70Tyr319/SykTyr352 antibody revealed that ZAP-70 is not phosphorylated at this site either before or after BCR stimulation, although in control experiments with Jurkat T-cells ZAP-70 became phosphorylated on Tyr319 upon TCR stimulation. Moreover, the Tyr352 site in Syk was phosphorylated following BCR stimulation in 6 of the 10 CLL B-cell samples. To further investigate the reasons for the unexpected lack of ZAP-70 activation in CLL B-cells, we produced stable transfectants of the BJAB lymphoma B-cell line that expressed ZAP-70 at levels similar to those found in CLL cases with progressive disease. In agreement with the CLL B-cell experiments, the Tyr319 site in ZAP-70 was not phosphorylated either before or after BCR stimulation. Since phosphorylation of Tyr319 is Lck-dependent in T-cells, and this kinase is expressed also in CLL B-cells, we ectopically expressed Lck in the ZAP-70-positive BJAB clones. Again, the Tyr319 site was not phosphorylated, indicating that ZAP-70 does not undergo activation of the kinase domain also in this cellular system. In contrast, BCR crosslinking in BJAB cells induced significant phosphorylation of Tyr352 in Syk, which was further enhanced in the clones that coexpressed ZAP-70. Furthermore, analysis of downstream signaling pathways following BCR stimulation showed stronger and prolonged activation of ERK and to a lesser extent Akt in the ZAP-70 positive clones, whereas no difference was observed in terms of activation of PLC-γ 2, JNK and degradation of the NF-kB inhibitor IkB. These data indicate that ZAP-70 does not undergo full activation in B-cells, but can still enhance activation of certain downstream BCR signaling pathways, possibly by affecting the activity of the related PTK Syk.

Monoclonal B-Cell Lymphocytosis (MBL) Is a Precursor State for Chronic Lymphocytic Leukemia (CLL) with 1% Progression Per Year.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 749-749
Author(s):  
Andy C. Rawstron ◽  
Fiona L. Bennet ◽  
Sheila J.M. O’Connor ◽  
Marwan Kwok ◽  
James A.L. Fenton ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Lymphocytic Leukemia ◽  
General Population ◽  
B Cell ◽  
Cell Count ◽  
Disease Progression ◽  
Lymphocyte Count ◽  
Progressive Disease ◽  
Lymphocytic Leukemia ◽  
Risk Of Disease

Abstract The 2007 IWCLL guidelines indicate that a diagnosis of Chronic Lymphocytic Leukemia (CLL) requires a B-cell count above 5,000/μL in the absence of other features; below this level the diagnosis is Monoclonal B-cell Lymphocytosis (MBL). There is little outcome data for MBL patients and it is not clear whether the detection of low levels of CLL cells, seen in 3% of the general population, is of clinical relevance. We have therefore investigated two hospital populations: the first with normal blood counts and no history of cancer; and the second MBL patients referred for investigation of a current or prior lymphocytosis. Blood samples from 1520 outpatients aged 60–80 with a normal blood count were screened: CLL cells were detected in 78/1520 (5.1%) with a median CLL cell count of 140/μL (range 15 – 1,248). Chromosomal abnormalities were frequently detected in purified CLL-phenotype cells (deletion 13q14 in 15/38, trisomy 12 in 4/22) although poor-risk abnormalities (deletion 11q or 17p) were not detected. The median IgVH mutation was 6.6% (range 0.5 – 13.7%) with 85% of cases showing >2% mutation from germline. The IgVH gene usage was heavily biased with a similar profile to mutated CLL. Detection of CLL cells in individuals with a normal count was not associated with increased mortality (estimated yearly rate 6.2% vs. 8.9% for matched controls, P=0.76) or risk of developing CLL as subsequent lymphocyte counts remained normal in all cases. A diagnosis of MBL was established in 309 of 2228 referrals for investigation of lymphocytosis between 1995 and 2000. A cohort of 185 MBL patients was monitored for a median 6.7 years (range 0.2 – 11.8): the presenting B-cell count was a median 3,100/μL (range 30 – 5,000), age 73 years (range 42 – 96); IgVH mutation rate was 7.1% (range 1.3 – 9.3%) with 96% of cases showing >2% mutation from germline. Progression to a lymphocyte count above 30,000/μL occurred in 15% of cases (28/185) and chemotherapy for progressive CLL was required in 7% (13/185). The absolute B-cell count was the only independent risk factor for an increasing disease levels. Neither IgVH mutation status nor CD38 expression predicted risk of disease progression or requirement for treatment. During follow-up 33% died: age above 70, hemoglobin concentration below 11 g/dL and T-lymphopenia (CD3+ <1,000/μL) predicted shorter survival, whereas patients presenting with a T-lymphocytosis (>2,400μL) had significantly longer survival. Development of progressive disease did not predict overall survival: 7/13 patients requiring therapy remain alive at a median 1.9 years (range 0–8.6 years) after initiation of treatment. The total lymphocyte count had no impact on the risk of disease progression, time to treatment or overall survival. CLL-phenotype cells are genetically equivalent to CLL even when detected in the general population but are not associated with increased mortality or risk of progression to CLL when present below 1,500/μL. MBL patients with higher levels of CLL cells show a steady increase in disease levels over time with 1–2% per year requiring chemotherapy for progressive disease. As such, periodic monitoring is indicated but this should have a minimal impact on lifestyle as MBL patients are often elderly with multiple health issues. MBL is a newly described disorder which is related to CLL in a similar way that MGUS is related to myeloma.

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