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PROVIDER: PRJNA138851 | ENA |
REPOSITORIES: ENA
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Project description:B-cell chronic lymphocytic leukemia (B-CLL) is a heterogenous disease with a highly variable clinical course and analysis of ZAP-70 and CD38 expression on B-CLL cells allowed for identification of patients with good (ZAP-70-CD38-), intermediate (discordant expression of ZAP-70 and CD38) and poor (ZAP-70+CD38+) prognosis. In an attempt to identify a molecular basis that may underly this diverse clinical behaviour DNA microarray technology was employed to compare eight ZAP-70+CD38+ with eight ZAP-70-CD38- B-CLL cases. We used microarrays to detail the global programme of gene expression distinguising B-CLL from patient with good (samples 1 to 8) and poor prognosis (sample 9 to 16) and identified distinct classes of up- and down-regulated genes. Keywords: Disease progression
2006-09-22 | GSE4392 | GEO
Project description:Glucocorticoids are part of the therapeutic armamentarium of chronic lymphocytic leukemia where it has been suggested that cells with unmutated IGHV genes exhibit higher sensitivity. The mechanisms by which glucorticoids are active in CLL are not well elucidated. We used microarrays to detail the global programme of gene expression underlying dexamethasone differential activity according to the prognostic subgroups mutated IGHV genes / low ZAP-70 expression and unmutated IGHV genes / high ZAP-70 expression. We aimed to ascertain the molecular mechanisms that are influencing the diffferential response to this drug. Peripheral blood mononuclear cells from chronic lymphocytic leukemia patients were obtained. Samples were split in two for control and incubation with dexamethasone for 6 hours. RNA was extracted and processed for further hybridization on Affymetrix microarrays.
2012-12-04 | E-GEOD-33135 | biostudies-arrayexpress
Project description:B-cell chronic lymphocytic leukemia (B-CLL) shows an incredibly high heterogeneity in the clinical course, spanning from rapidly aggressive to completely indolent behaviour. In order to identify the correspondent gene expression variability, we investigated 29 cases of untreated B-CLL using microarray. Firstly, two robust CLL clusters were identified applying multiple unsupervised clustering algorithms. Their separation was mainly determined by the differential expression of several genes included into two gene groups designated OxPhos and Lyn clusters. OxPhos gene cluster, previously identified in a subset of diffuse large B-cell lymphomas, comprises genes coding for some respiratory chain enzymes, ribosomal proteins and translation factors. Moreover, increased levels of genes involved in the regulation of apoptosis and in the proteasome-ubiquitin complex and the down-regulation of LYN gene, member of B-cell receptor pathway, characterized the OxPhos CLL subset. These B-CLL biological clusters did not reveal any preferential distribution of Ig mutated or Ig unmutated CLL prognostic groups. Furthermore, we applied another unsupervised algorithm (Subtractive Unsupervised Analysis) after the exclusion of genes characterizing the previously identified CLL subsets. At this point, we could identify two new CLL clusters, showing a clear association to the Ig mutational status. In addition to the ZAP-70 and LPL genes, the patients with unmutated Ig expressed higher level of some interesting genes involved in B cell activation, cell cycle regulation, apoptosis resistance and angiogenesis. In conclusion, we showed that B-CLL is characterized by an intrinsic heterogeneity in gene expression pattern, which overcomes the influence of the immunoglobulin mutational status on B-cell chronic lymphocytic leukemia profiles. Keywords: chronic lymphocytic leukemia, gene expressione profile, immunuglobulin mutational status, clinical heterogeneity
2006-02-25 | GSE4207 | GEO
Project description:B-cell chronic lymphocytic leukemia (B-CLL) is a heterogenous disease with a highly variable clinical course and analysis of ZAP-70 and CD38 expression on B-CLL cells allowed for identification of patients with good (ZAP-70-CD38-), intermediate (discordant expression of ZAP-70 and CD38) and poor (ZAP-70+CD38+) prognosis. In an attempt to identify a molecular basis that may underly this diverse clinical behaviour DNA microarray technology was employed to compare eight ZAP-70+CD38+ with eight ZAP-70-CD38- B-CLL cases. We used microarrays to detail the global programme of gene expression distinguising B-CLL from patient with good (samples 1 to 8) and poor prognosis (sample 9 to 16) and identified distinct classes of up- and down-regulated genes. Experiment Overall Design: To compare the transcriptosomes of good prognosis CLL cases (ZAP-70-CD38-) to poor prognosis cases (ZAP-70+CD38+), we purified CD19+ cells from peripheral blood samples by immunomagnetic isolation using MidiMacs, resulting in >95% purity of leukemic cells as detected by FACS analysis of CD19+CD5+ cells. The leukemic cells were freshly purified from untreated patients and RNA was directly isolated from fresh cells without further ex vivo treatment of the cells. Eight immunomagnetically purified peripheral blood derived ZAP-70+CD38+ CLL cases were compared with eight ZAP-70-CD38- B-CLL cases.
2009-04-23 | E-GEOD-4392 | biostudies-arrayexpress
Project description:Chronic lymphocytic leukemia (CLL) is a disease with a highly variable prognosis. The clinical course can however be predicted thanks to prognostic markers. Poor prognosis is associated with expression of a B cell receptor (BCR) from unmutated immunoglobulin variable heavy-chain genes (IgVH) and expression of zeta associated protein of 70 kDa (ZAP-70). The reason why ZAP-70 expression is associated with poor prognosis and whether the protein has a direct pathogenic function is at present unknown. By transfer of ZAP-70 to CLL cells, we show here that expression of ZAP-70 in CLL cells leads to increased expression of the NF-M-NM-:B target genes interleukin-1M-NM-2 (IL-1M-NM-2), IL-6 and IL-8 upon BCR triggering. This could be blocked by inhibition of NF-M-NM-:B signaling through inhibition of IM-NM-:B kinases (IKK). Transcriptome analysis identified a NF-M-NM-:B RelA signature imposed by ZAP-70 expression in BCR stimulated CLL cells. We conclude that ZAP-70 acts directly as an amplifier of NF-M-NM-:B signaling in CLL cells which could be an underlying mechanism for its association with poor prognosis and which may represent a therapeutic target. 22 patient samples, Stimulated for 3h or 24h, Electroporated with capped ZAP-70 mRNA or uncapped ZAP-70 mRNA (negative control)
2013-10-22 | E-GEOD-51286 | biostudies-arrayexpress
Project description:Chronic lymphocytic leukemia (CLL) is a disease with a highly variable prognosis. The clinical course can however be predicted thanks to prognostic markers. Poor prognosis is associated with expression of a B cell receptor (BCR) from unmutated immunoglobulin variable heavy-chain genes (IgVH) and expression of zeta associated protein of 70 kDa (ZAP-70). The reason why ZAP-70 expression is associated with poor prognosis and whether the protein has a direct pathogenic function is at present unknown. By transfer of ZAP-70 to CLL cells, we show here that expression of ZAP-70 in CLL cells leads to increased expression of the NF-κB target genes interleukin-1β (IL-1β), IL-6 and IL-8 upon BCR triggering. This could be blocked by inhibition of NF-κB signaling through inhibition of IκB kinases (IKK). Transcriptome analysis identified a NF-κB RelA signature imposed by ZAP-70 expression in BCR stimulated CLL cells. We conclude that ZAP-70 acts directly as an amplifier of NF-κB signaling in CLL cells which could be an underlying mechanism for its association with poor prognosis and which may represent a therapeutic target.
2013-10-22 | GSE51286 | GEO
Project description:B cell chronic lymphocytic leukemia - A model with immune response
Seema Nanda 1, , Lisette dePillis 2, and Ami Radunskaya 3,
1.
Tata Institute of Fundamental Research, Centre for Applicable Mathematics, Bangalore 560065, India
2.
Department of Mathematics, Harvey Mudd College, Claremont, CA 91711
3.
Department of Mathematics, Pomona College, Claremont, CA, 91711, United States
Abstract
B cell chronic lymphocytic leukemia (B-CLL) is known to have substantial clinical heterogeneity. There is no cure, but treatments allow for disease management. However, the wide range of clinical courses experienced by B-CLL patients makes prognosis and hence treatment a significant challenge. In an attempt to study disease progression across different patients via a unified yet flexible approach, we present a mathematical model of B-CLL with immune response, that can capture both rapid and slow disease progression. This model includes four different cell populations in the peripheral blood of humans: B-CLL cells, NK cells, cytotoxic T cells and helper T cells. We analyze existing data in the medical literature, determine ranges of values for parameters of the model, and compare our model outcomes to clinical patient data. The goal of this work is to provide a tool that may shed light on factors affecting the course of disease progression in patients. This modeling tool can serve as a foundation upon which future treatments can be based.
Keywords: NK cell, chronic lymphocytic leukemia, mathematical model, T cell., B-CLL.
2020-01-09 | MODEL2001090002 | BioModels
Project description:Gene expression profile after dexamethasone in chronic lymphocytic leukemia cells according to IGHV/ZAP-70 status
| PRJNA149407 | ENA
Project description:Glucocorticoids are part of the therapeutic armamentarium of chronic lymphocytic leukemia where it has been suggested that cells with unmutated IGHV genes exhibit higher sensitivity. The mechanisms by which glucorticoids are active in CLL are not well elucidated. We used microarrays to detail the global programme of gene expression underlying dexamethasone differential activity according to the prognostic subgroups mutated IGHV genes / low ZAP-70 expression and unmutated IGHV genes / high ZAP-70 expression. We aimed to ascertain the molecular mechanisms that are influencing the diffferential response to this drug.
2012-12-04 | GSE33135 | GEO
Project description:Several studies demonstrated IgVH mutation status and ZAP-70 expression as the most relevant prognostic markers in CLL, suggesting the separation of two patient subgroups: with good (MTZAP-70-) and poor prognosis (UMZAP-70+). We determined gene expression of B cells in 112 CLL patients divided into three classes: the first with IgVHMT and ZAP-70-, the second with IgVHUM and ZAP-70+, and the third included both IgVHUM ZAP-70- and IgVHMT ZAP-70+. We found LPL, AGPAT2, MBOAT1, CHPT1, AGPAT4, PLD1 genes encoding enzymes involved in lipid (glycerolipid/glycerophospholipid) metabolism overexpressed in UMZAP-70+. In addition, this study demonstrates the role of ARSD, a gene belonging to the sphingolipid metabolism, as a new gene significantly overexpressed in UMZAP-70+ in respect to MTZAP-70-. ARSD protein was found at significantly higher concentrations in UMZAP-70+ compared to MTZAP-70- CLL B cells and B cells from healthy individuals by Western blotting. Statistical analysis identified a strong correlation between ARSD and IgVH mutation status; ARSD protein level was associated with the requirement of therapy for CLL patients and for this purpose it is as good as IgVH mutational status. Our study highlights ARSD as a promising new prognostic factor in CLL and sphingolipid metabolism as a putative new biological mechanism in CLL. In this study we performed gene expression profiling of B cells on 112 CLL patients divided into three classes based on IgVH mutational status and ZAP-70 protein expression: class one with mutated IgVH and ZAP-70-, class two with unmutated IgVH and ZAP-70+, and class three included CLL patients with unmutated IgVH and ZAP-70-, or mutated IgVH and ZAP-70+, respectively. The decision to divide CLL patients in three categories was due to the clinical feature and the molecular heterogeneity of CLL, in order to elaborate different molecular signature capable of reveal biological mechanisms, and to identify new potential molecular predictors for prognostic assessment or genetic risk. RNA was extracted and quantified for high-density oligonucleotide microarrays Human Genome U133 Plus 2.0 GeneChip (Affymetrix, Santa Clara, CA). A first cohort of 62 subjects was analyzed using GeneChip Expression 3' Amplification One-Cycle Target Labeling Kit, while a second cohort of 50 subjects using GeneChip 3'IVT Express Kit, according to manufacturerM-bM-^@M-^Ys protocol (Affymetrix), respectively.
2015-01-12 | E-GEOD-28654 | biostudies-arrayexpress