The clinical significance of NOTCH1 and SF3B1 mutations in the UK LRF CLL4 trial

Blood ◽  
2013 ◽  
Vol 121 (3) ◽  
pp. 468-475 ◽  
Author(s):  
David G. Oscier ◽  
Matthew J. J. Rose-Zerilli ◽  
Nils Winkelmann ◽  
David Gonzalez de Castro ◽  
Belen Gomez ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Controlled Clinical Trial ◽  
Cd38 Expression ◽  
Trisomy 12 ◽  
The Uk ◽  
Relationship Of ◽  
The Impact ◽  
The Relationship

Abstract NOTCH1 and SF3B1 mutations have been previously reported to have prognostic significance in chronic lymphocytic leukemia but to date they have not been validated in a prospective, controlled clinical trial. We have assessed the impact of these mutations in a cohort of 494 patients treated within the randomized phase 3 United Kingdom Leukaemia Research Fund Chronic Lymphocytic Leukemia 4 (UK LRF CCL4) trial that compared chlorambucil and fludarabine with and without cyclophosphamide in previously untreated patients. We investigated the relationship of mutations in NOTCH1 (exon 34) and SF3B1 (exon 14-16) to treatment response, survival and a panel of established biologic variables. NOTCH1 and SF3B1 mutations were found in 10% and17% of patients, respectively. NOTCH1 mutations correlated with unmutated IGHV genes, trisomy 12, high CD38/ ZAP-70 expression and were associated with reduced overall (median 54.8 vs 74.6 months, P = .02) and progression-free (median 22.0 vs 26.4 months, P = .02) survival. SF3B1 mutations were significantly associated with high CD38 expression and with shorter overall survival (median 54.3 vs 79.0 months, P < .001). Furthermore, multivariate analysis, including baseline clinical variables, treatment, and adverse prognostic factors demonstrated that although TP53 alterations remained the most informative marker of dismal survival in this cohort, NOTCH1 (HR 1.58, P = .03) and SF3B1 (HR 1.52, P = .01) mutations have added independent prognostic value.

scholarly journals The Impact and Prognostic Significance of Chronic Lymphocytic Leukemia Upregulated 1 (CLLU1) Gene Expression in Patients with Chronic Lymphocytic Leukemia: A Single Center Experience

2019 ◽  
Vol 51 (3) ◽  
pp. 259-264
Author(s):  
Mustafa Sevinc ◽  
Aydın Karabulut ◽  
Ahmet Emre Eskazan ◽  
Suzin Catal Tatonyan ◽  
Ugur Ozbek ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Prognostic Parameters ◽  
Single Center Experience ◽  
Polymerase Chain ◽  
Cluster Of Differentiation ◽  
Relationship Of ◽  
The Impact ◽  
The Relationship

Abstract Objectives To determine CLLU1 gene levels and the relationship of that gene among other prognostic parameters in patients with chronic lymphocytic leukemia. Methods Bone-marrow infiltration pattern, β2-microglobulin (β 2-M), cluster of differentiation (CD)38, and ZAP-70 status were recorded. CLLU1 levels were assessed by real-time polymerase chain reaction (RT-PCR) and expressed as folds. The relationship between CLLU1 and other known prognostic parameters was evaluated. Results CLLU1 expression was positive in 81 patients and negative in 3 patients. The median (interquartile range [IQR]) CLLU1 level was 6.45 folds (3.75–16.57 folds) in patients with β 2-M normal values and 16.22 folds (3.91–62.00 folds) in patients with increased β 2-M (P = .15). Patients with a higher CD38 value than the median level had 3 times higher CLLU1 levels than the other group (P = .07). The median (IQR) CLLU1 level was 4.25 folds (2.75–13.71 folds) in patients with CLL who tested negative on ZAP-70, whereas it was 49.52 folds (15.06–446.36 folds) in those who tested positive via ZAP-70 (P = .005). Conclusions CLLU1 is a specific parameter to CLL, and its level corresponds well with the ZAP-70 level.

scholarly journals A high-resolution allelotype of B-cell chronic lymphocytic leukemia (B-CLL)

Blood ◽  
2002 ◽  
Vol 100 (5) ◽  
pp. 1787-1794 ◽  
Author(s):  
Urban Novak ◽  
Elisabeth Oppliger Leibundgut ◽  
Jörg Hager ◽  
Dominique Mühlematter ◽  
Martine Jotterand ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Chromosomal Aberrations ◽  
Cytogenetic Analysis ◽  
Prognostic Significance ◽  
Genetic Alterations ◽  
Lymphocytic Leukemia ◽  
Accurate Information ◽  
Trisomy 12 ◽  
Cell Chronic Lymphocytic Leukemia

The most frequent chromosomal aberrations in B-cell chronic lymphocytic leukemia (B-CLL) are deletions on 13q, 11q, and 17p, and trisomy 12, all of which are of prognostic significance. Conventional cytogenetic analysis and fluorescence in situ hybridization (FISH) are used for their detection, but cytogenetic analysis is hampered by the low mitotic index of B-CLL cells, and FISH depends on accurate information about candidate regions. We used a set of 400 highly informative microsatellite markers covering all chromosomal arms (allelotyping) and automated polymerase chain reaction (PCR) protocols to screen 46 patients with typical B-CLL for chromosomal aberrations. For validation, we compared data with our conventional karyotype results and fine mapping with conventional single-site PCR. All clonal cytogenetic abnormalities potentially detectable by our microsatellite PCR (eg, del13q14 and trisomy 12) were picked up. Allelotyping revealed additional complex aberrations in patients with both normal and abnormal B-CLL karyotypes. Aberrations detectable in the samples with our microsatellite panel were found on almost all chromosomal arms. We detected new aberrant loci in typical B-CLL, such as allelic losses on 1q, 9q, and 22q in up to 25% of our patients, and allelic imbalances mirroring chromosomal duplications, amplifications, or aneuploidies on 2q, 10p, and 22q in up to 27% of our patients. We conclude that allelotyping with our battery of informative microsatellites is suitable for molecular screening of B-CLL. The technique is well suited for analyses in clinical trials, it provides a comprehensive view of genetic alterations, and it may identify new loci with candidate genes relevant in the molecular biology of B-CLL.

scholarly journals The Study of Religion in the UK in its Institutional Context

2017 ◽  
Vol 71 (1) ◽  
pp. 44-57
Author(s):  
Kim Knott
Keyword(s):  
Public Funding ◽  
Subject Area ◽  
Institutional Pressures ◽  
The Public ◽  
Institutional Structures ◽  
Institutional Contexts ◽  
The Uk ◽  
Relationship Of ◽  
The Impact ◽  
The Relationship

Abstract How has the study of religion in the UK been shaped by its institutional contexts? Consideration is given to the Christian and secular foundations of universities and higher education colleges, the relationship of theology and religious studies, and the impact of institutional structures and drivers associated with teaching and research. The formation of ‘TRS’ as an instrumental and contested subject area is discussed, as is the changing curriculum. Research on religion is examined in relation to new institutional pressures and opportunities: the assessment of university research and the public funding of research. The importance of the impact agenda and capacity building are illustrated.

scholarly journals Leukemic-like membrane properties acquired by B lymphocytes when depleted of 185,000-dalton macromolecular insoluble cold globulin

Blood ◽  
1982 ◽  
Vol 59 (3) ◽  
pp. 555-562
Author(s):  
MA Simmonds ◽  
G Sobczak ◽  
SP Hauptman
Keyword(s):  
B Cells ◽  
Chronic Lymphocytic Leukemia ◽  
Human Peripheral Blood ◽  
Present Report ◽  
Peripheral Blood Lymphocytes ◽  
Lymphocytic Leukemia ◽  
Leukemic Cells ◽  
Membrane Properties ◽  
Relationship Of ◽  
The Relationship

Human peripheral blood lymphocytes can be phenotypically identified by the presence of one or both of two proteins, 225,000-dalton macromolecular insoluble cold globulin (225-MICG) and 185,000-dalton MICG (185-MICG). T cells synthesize and insert into their plasma membrane 225-MICG, null cells 185-MICG, and B cells both 225 and 185- MICG. In contrast, the monoclonal B cells of chronic lymphocytic leukemia are characterized by the presence of 225-MICG and the absence of 185-MICG. We have recently found it possible to chemically deplete 185-MICG from viable normal B cells by treating them with diisopropylfluorophosphate (DFP), thus making normal B cells phenotypically resemble leukemic cells. In the present report we determined whether certain peculiar properties of these leukemic cells would be associated with the normal B cells chemically depleted of 185- MICG. In normal B cells, SIg diffuses in the lipid bilayer to form clusters and caps under appropriate conditions, while in chronic lymphocytic leukemia (CLL) cells this does not occur. Normal B cells depleted of 185-MICG fail to undergo capping of SIg or surface MICG under appropriate conditions. Both DFP-treated B cells and CLL cells tend to rupture when smeared on a glass slide. Both CLL cells and DFP- treated B cells fail to secrete 225-MICG after it has been synthesized intracellularly. The relationship of these findings to the mechanisms of secretion and capping are discussed.

The impact of trisomy 12, retinoblastoma gene and P53 in prognosis of B-cell chronic lymphocytic leukemia

Hematology ◽  
2008 ◽  
Vol 13 (3) ◽  
pp. 147-153 ◽  
Author(s):  
M. AbdelSalam ◽  
A. El Sissy ◽  
M. A. Samra ◽  
S. Ibrahim ◽  
D. El Markaby ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Lymphocytic Leukemia ◽  
Retinoblastoma Gene ◽  
Trisomy 12 ◽  
The Impact ◽  
Cell Chronic Lymphocytic Leukemia

Comprehensive Assessment of Genetic and Molecular Features Predicting Outcome in Patients With Chronic Lymphocytic Leukemia: Results From the US Intergroup Phase III Trial E2997

2007 ◽  
Vol 25 (7) ◽  
pp. 799-804 ◽  
Author(s):  
Michael R. Grever ◽  
David M. Lucas ◽  
Gordon W. Dewald ◽  
Donna S. Neuberg ◽  
John C. Reed ◽  
...  
Keyword(s):  
Chronic Lymphocytic Leukemia ◽  
Prognostic Significance ◽  
Variable Region ◽  
Hazard Ratio ◽  
Lymphocytic Leukemia ◽  
Phase Iii ◽  
Therapeutic Trial ◽  
Cd38 Expression ◽  
Molecular Features ◽  
Mutational Status

Purpose Genomic features including unmutated immunoglobulin variable region heavy chain (IgVH) genes, del(11q22.3), del(17p13.1), and p53 mutations have been reported to predict the clinical course and overall survival of patients with chronic lymphocytic leukemia (CLL). In addition, ZAP-70 and Bcl-2 family proteins have been explored as predictors of outcome. Patients and Methods We prospectively evaluated the prognostic significance of a comprehensive panel of laboratory factors on both response and progression-free survival (PFS) using samples and data from 235 patients enrolled onto a therapeutic trial. Patients received either fludarabine (FL; n = 113) or fludarabine plus cyclophosphamide (FC; n = 122) as part of a US Intergroup randomized trial for previously untreated CLL patients. Results Complete response (CR) rates were 24.6% for patients receiving FC and 5.3% for patients receiving FL (P = .00004). PFS was statistically significantly longer in patients receiving FC (median, 33.5 months for patients receiving FC and 19.9 months for patients receiving FL; P < .0001). The occurrence of del(17p13.1) (hazard ratio, 3.428; P = .0002) or del(11q22.3) (hazard ratio, 1.904; P = .006) was associated with reduced PFS. CR and overall response rates were not significantly different based on cytogenetics, IgVH mutational status, CD38 expression, or p53 mutational status. Expression of ZAP-70, Bcl-2, Bax, Mcl-1, XIAP, Caspase-3, and Traf-1 was not associated with either clinical response or PFS. Conclusion These results support the use of interphase cytogenetic analysis, but not IgVH, CD38 expression, or ZAP-70 status, to predict outcome of FL-based chemotherapy. Patients with high-risk cytogenetic features should be considered for alternative therapies.

Higher BTK-Dependent Cell Proliferation in Unmutated Chronic Lymphocytic Leukemia Confers Increased Sensitivity to Ibrutinib

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5296-5296
Author(s):  
Ailin Guo ◽  
Pin Lu ◽  
Natalie Galanina ◽  
Chadi Nabhan ◽  
Sonali M. Smith ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Chronic Lymphocytic Leukemia ◽  
Prognostic Significance ◽  
Lymphocytic Leukemia ◽  
Prognostic Impact ◽  
Region Gene ◽  
Bcr Signaling ◽  
Dependent Cell ◽  
Increased Sensitivity ◽  
The Impact

Abstract In chronic lymphocytic leukemia (CLL), mutation status of the immunoglobulin heavy chain variable region gene (IGHV) has prognostic significance, with the unmutated phenotype (UM-CLL) having worse outcomes than mutated CLL (M-CLL) following chemotherapy or chemoimmunotherapy. However, in the era of BCR-targeted therapies, the adverse prognostic impact of unmutated IGHV seems to be diminishing, and there are clinical datasets showing unexpected improved responses in UM-CLL. We investigated the biological differences of BTK activity between these subgroups and further compared the impact of ibrutinib on molecular and cellular behaviors. Immunoblotting analysis revealed that phosphorylated active BTK. is significantly higher in UM-CLL. Moreover, UM-CLL, compared to M-CLL, displayed a much higher proliferative capacity that was associated with greater sensitivity to ibrutinib. In addition, BTK depletion with siRNA led to a more prominent reduction in the proliferation of UM-CLL, suggesting that elevated BTK activity is responsible for increased cell proliferation. Further, cell signaling activity by multiple measurements was consistently higher in UM-CLL accompanied by a higher sensitivity to ibrutinib. These studies link UM-CLL to elevated BCR signaling, higher BTK-dependent cell proliferation and increased sensitivity to ibrutinib. The prognostic significance of IGHV mutation should be reevaluated in the era of new therapies targeting BCR signaling. Disclosures Nabhan: Celgene Corporation: Honoraria, Research Funding. Smith:Celgene: Consultancy; Pharmacyclics: Consultancy.

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