Homo sapiens
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PROVIDER: PRJNA94581 | 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. 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: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:The expression of ZAP-70 in a subset of CLL patients strongly correlates with a more aggressive clinical course, though the exact underlying mechanisms remain elusive. The ability of ZAP-70 to enhance B cell receptor (BCR) signaling, independently of its kinase function, likely contributes. Here we employed RNA-sequencing and proteomic analyses of primary cells and cell lines, differing only in their expression of ZAP-70, to further define how ZAP-70 increases aggressiveness of CLL. We identified that ZAP-70 is required for the constitutive expression of T cell chemokines and the MHC class I molecule CD1c in the absence of an overt BCR signal, both promoting interactions with T cells. In addition, quantitative mass spectrometry of double-cross linked ZAP-70 complexes demonstrated that direct protein-protein interactions between ZAP-70 and cytoskeletal proteins positively regulate cell migration, irrespectively of CCR7 expression. Importantly, these functions of ZAP-70 did not require antigen-stimulation of the BCR. In contrast, we observed that ZAP-70 rapidly forms complexes with ribosomal proteins in BCR-activated cells, while decreasing the expression of ZAP-70 significantly reduced protein biosynthesis, providing evidences that ZAP-70 contributes to translational dysregulation in CLL. In conclusion, ZAP-70 promotes microenvironment-interactions and protein-translation in CLL cells, both likely to improve cellular fitness and to further drive disease progression.
2022-08-26 | PXD019465 | Pride
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: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.
2015-01-12 | GSE28654 | GEO
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: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
Project description:We describe 9 CLL patients who underwent a spontaneous clinical regression. CD38 and ZAP-70 were negative in all cases. Immunoglobulin heavy chain variable region (IgVH) genes, mutated in all 7 evaluable patients, were restricted to the VH3 family in 6, with the usage of VH3-30 gene in 2. The light chain variable region genes were mutated in 6/8 cases, with the usage of Vκ4-1 gene in 3. Microarray analysis of CLL cells revealed a distinctive genomic profile. The number of activated T lymphocytes expressing IFN-γ, TNF-α and IL-4 was similar between CLL in spontaneous regression and healthy individuals.
2009-04-22 | GSE15777 | GEO
Project description:RNA seq profiles of primary CLL cells transfected with non-specific control (NSC) or ZAP-70 siRNA ± anti-IgM. This submission is +anti-IgM.
2022-04-19 | GSE149021 | GEO