Molecular heterogeneity in chronic lymphocytic leukemia is dependent on BCR signaling: clinical correlation

Rodríguez, Antonia; Villuendas, Raquel; Yáñez, Lucrecia; Gómez, María R.; Díaz, Raquel; Pollán, Marina; Hernández, N; Cueva, P. de la; Marin, Miguel; Swat, Aneta; Ruiz, Erazo; Cuadrado, M A; Conde, Eulogio; Lombardía, Luís; Cifuentes, Francisco Tejada; González, Marcos; García-Marco, José A.; Piris, Miguel Á.

doi:10.1038/sj.leu.2404831

Cited by 55 publications

(55 citation statements)

References 34 publications

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“…17 The miRNA microarray experiments were done using the Agilent Human miRNA Microarray (V1), 8 Â 15 K (Agilent Technologies). For each tissue sample, 100 ng total RNA were hybridized with the miRNA array and further processed as previously described.…”

Section: Rna Isolationmentioning

confidence: 99%

Splenic marginal zone lymphoma: comprehensive analysis of gene expression and miRNA profiling

et al. 2013

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Splenic marginal zone lymphoma is a small B-cell neoplasm whose molecular pathogenesis is still essentially unknown and whose differentiation from other small B-cell lymphomas is hampered by the lack of specific markers. We have analyzed the gene expression and miRNA profiles of 31 splenic marginal zone lymphoma cases. For comparison, 7 spleens with reactive lymphoid hyperplasia, 10 spleens infiltrated by chronic lymphocytic leukemia, 12 spleens with follicular lymphoma, 6 spleens infiltrated by mantle cell lymphoma and 15 lymph nodes infiltrated by nodal marginal zone lymphoma were included. The results were validated by qRT-PCR in an independent series including 77 paraffin-embedded splenic marginal zone lymphomas. The splenic marginal zone lymphoma miRNA signature had deregulated expression of 51 miRNAs. The most highly overexpressed miRNAs were miR-155, miR-21, miR-34a, miR-193b and miR-100, while the most repressed miRNAs were miR-377, miR-27b, miR-145, miR-376a and miR-424. MiRNAs located in 14q32-31 were underexpressed in splenic marginal zone lymphoma compared with reactive lymphoid tissues and other B-cell lymphomas. Finally, the gene expression data were integrated with the miRNA profile to identify functional relationships between genes and deregulated miRNAs. Our study reveals miRNAs that are deregulated in splenic marginal zone lymphoma and identifies new candidate diagnostic molecules for splenic marginal zone lymphoma.

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Section: Rna Isolationmentioning

confidence: 99%

Splenic marginal zone lymphoma: comprehensive analysis of gene expression and miRNA profiling

et al. 2013

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“…The functional relevance of TCL1A expression was validated by analyzing a previously published independent series of 98 chronic lymphocytic leukemia 22 patients with Gene-Set Enrichment Analysis. Cases that strongly expressed TCL1A, more strongly expressed genes clustered in the gene sets identified as BLIMP-1 targets and the CREBP pathway, including important B-cell receptor signaling genes such as SYK, BTK, and AKT-1.…”

Section: Tcl1a Expression In B-cell Non-hodgkin's Lymphomamentioning

confidence: 99%

TCL1A expression delineates biological and clinical variability in B-cell lymphoma

et al. 2009

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The assembly of a collection of gene-expression signatures of the major types of B-cell non-Hodgkin's lymphoma has identified increased T-cell leukemia/lymphoma 1A (TCL1) expression in multiple lymphoma types and cases, and has enabled the investigation of the functional and clinical importance of TCL1 expression. Specifically, Burkitt's lymphoma cases show a homogeneously strong expression of TCL1, whereas diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia, nodal marginal zone lymphoma, and splenic marginal zone lymphoma display a striking variability in the intensity of TCL1 staining. This was validated in two independent series. A Gene-Set Enrichment Analysis of the genes correlated with TCL1A expression found that variation in the level of expression of TCL1A was significantly associated with some of the most important gene signatures recognizing B-cell lymphoma pathogenesis and heterogeneity, such as germinal center, B-cell receptor, NF-jB (and its target genes), death, MAP kinases, TNFR1, TOLL, and IL1R. Additionally, TCL1 expression was correlated with shorter time to treatment in chronic lymphocytic leukemia cases and shorter lymphoma-specific survival in mantle cell lymphoma series, thus indicating the clinical and biological significance of TCL1 expression, and suggesting TCL1A as a potential therapeutic target.

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“…They can therefore have an inhibitory role in BCR 30 or in MAPK signaling. 31 Stimuli given by the microenvironment could confer growth advantage and extended survival to leukemic cells. 32 Moreover, BCR stimulation is linked to cell survival, activation, and G1 progression.…”

Section: Cd38mentioning

confidence: 99%

Gene expression profiling reveals differences in microenvironment interaction between patients with chronic lymphocytic leukemia expressing high versus low ZAP70 mRNA

Stamatopoulos¹,

Haibe‐Kains²,

Equeter³

et al. 2009

Haematologica

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The online version of this article contains a supplementary appendix.Background Zeta-associated protein 70 (ZAP70) is a widely recognized prognostic factor in chronic lymphocytic leukemia, but mechanisms by which its higher expression leads to a poor outcome must still be fully explained. Design and MethodsIn an attempt to unveil unfavorable cellular properties linked to high ZAP70 expression, we used gene expression profiling to identify genes associated with disparities in B cells from chronic lymphocytic leukemia patients expressing high versus low ZAP70 mRNA, measured by quantitative real-time PCR. Two groups of 7 patients were compared, selected on the basis of either high or low ZAP70 mRNA expression. ResultsTwenty-seven genes were differentially expressed with an FDR<10%, and several genes were significant predictors of treatment-free survival (TFS) and/or overall survival; PDE8A and FCRL family genes (down-regulated in ZAP70 + patients) could predict TFS and overall survival; ITGA4 mRNA (up-regulated in ZAP70 + patients) could significantly predict overall survival. Importantly, gene set enrichment analysis revealed overrepresentation of adhesion/migration genes. We therefore investigated in vitro adhesion/migration capacity of chronic lymphocytic leukemia cells into a stromal microenvironment or in response to conditioned medium. We showed that ZAP70 + cells had better adhesion/migration capacities and only ZAP70 + patient cells responded to microenvironment contact by CXCR4 downregulation. ConclusionsWe concluded that several prognostic factors are the reflection of microenvironment interactions and that the increased adhesion/migratory capacity of ZAP70 + cells in their microenvironment can explain their better survival and thus the aggressiveness of the disease.Key words: chronic lymphocytic leukemia, ZAP70, microarrays, microenvironment, prognosis.Citation: Stamatopoulos B, Haibe-Kains B, Equeter C, Meuleman N, Sorée A, De Bruyn C, Hanosset D, Bron D, Martiat P, and Lagneaux L. Gene expression profiling reveals differences in microenvironment interaction between patients with chronic lymphocytic leukemia expressing high versus low ZAP70 mRNA. Haematologica 2009; 94:790-799. doi:10.3324/haematol.2008 This is an open-access paper.Gene expression profiling reveals differences in microenvironment interaction between patients with chronic lymphocytic leukemia expressing high versus low ZAP70 mRNA

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Molecular heterogeneity in chronic lymphocytic leukemia is dependent on BCR signaling: clinical correlation

Cited by 55 publications

References 34 publications

Splenic marginal zone lymphoma: comprehensive analysis of gene expression and miRNA profiling

Splenic marginal zone lymphoma: comprehensive analysis of gene expression and miRNA profiling

TCL1A expression delineates biological and clinical variability in B-cell lymphoma

Gene expression profiling reveals differences in microenvironment interaction between patients with chronic lymphocytic leukemia expressing high versus low ZAP70 mRNA

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