Differential Gene Expression Profile Associated to Apoptosis Induced by Dexamethasone in CLL Cells According to IGHV/ZAP-70 Status

Baptista, Maria Joao; Muntañola, Ana; Calpe, Eva; Salamero, Olga; Fernández, Eva; Codony, Carles; Giné, Eva; Kalko, Susana G.; Crespo, Marta; Bosch, Francesc

doi:10.1158/1078-0432.ccr-11-2771

Cited by 5 publications

(3 citation statements)

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“…Dexamethasone (DEX) triggers apoptosis by either transactivation through the glucocorticoid response element (GRE), transrepression of NF-kappaB, phosphorylation of intracytoplasmic tyrosine kinase RAFTK, or induction of BCL2L11 ( BIM ) gene [ 26 ]. Moreover, since 1940 s, when GCs were introduced as first systemic therapy for CLL patients, it is known that they interfere with leukemic lymphocytes homing and redistribution between blood and secondary lymphoid tissues [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…BCL2 itself is considered as very attractive target of the therapy in many types of cancer. First attempts with oblimersen ( BCL2 antisense phosphorothioate oligodeoxynucleotide G3139) and Oblataclax (BH3 mimetic BCL2 inhibitor GX15-070) were not very successful in CLL [ 26 ]. The results of the phase I study of Navitoclax (ABT-263, disruptor of BCL2–BCL-xL interactions with pro-apoptotic proteins) in patients with relapsed or refractory CLL were more promising, but it caused thrombocytopenia due to BCL-xL inhibition [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

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Guilty bystanders: nurse-like cells as a model of microenvironmental support for leukemic lymphocytes

2013

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B-cell chronic lymphocytic leukemia (B-CLL) is one of the most common leukemias among the elderly and, despite many efforts, still stays incurable. Recent studies point to the microenvironment as the critical factor providing leukemic lymphocytes with pro-survival signals. Thus, the neighboring cells appear to be a perfect target for antileukemic therapy. Nurse-like cells (NLCs) largely contribute to CLL microenvironmental support. We developed the CLL lymphocyte/NLC co-culture model for the investigation of microenvironmental interactions. Viability and apoptosis were investigated in CLL lymphocytes treated with dexamethasone (DEX) and chlorambucil (CLB), with and without NLCs’ support. For the first time, the capacity of DEX and CLB to affect NLCs viability was also evaluated. Apoptosis-associated gene expression profiles of leukemic lymphocytes ex vivo and cultured with NLCs were assessed by expression arrays. CLL lymphocytes escaped spontaneous apoptosis for several months when cultured with NLCs. The presence of NLCs significantly reduced apoptosis induced with DEX and CLB (p < 0.001; p = 0.012, respectively), and their protective effect was more evident than the effect of recombinant SDF1. Both DEX and CLB also decreased NLCs viability, but to a lesser extent (mean viability in DEX-treated cultures was 37.79 % in NLCs compared to 29.24 % in lymphocytes). NLCs induced the expression of important anti-apoptotic genes in cultured CLL lymphocytes; median expression of BCL2, SURVIVIN, BCL2A1, and XIAP was significantly higher as compared to ex vivo status. The CLL lymphocyte/NLC co-culture makes up the convenient and close to the natural-state model for studying the relationship between leukemic cells and the microenvironment. Direct cell-to-cell contact with NLCs increases the expression of anti-apoptotic genes in CLL lymphocytes, thus protecting them against induced apoptosis. As the effect of antileukemic drugs is not so apparent in NLCs, the combined therapy targeted at both lymphocytes and the microenvironment should be considered for CLL patients. Simultaneous aiming at the disruption of several different signaling pathways and/or anti-apoptotic proteins may further improve treatment efficiency.Electronic supplementary materialThe online version of this article (doi:10.1007/s10238-013-0268-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Guilty bystanders: nurse-like cells as a model of microenvironmental support for leukemic lymphocytes

2013

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“…The resistance was correlated with reduced histone H3 acetylation and could be overcome by the HDAC inhibitor vorinostat [ 522 ]. Also, Bim induction in chronic lymphocytic leukemia in response to glucocorticoids correlated with the response rate [ 637 ].…”

Section: Therapeutic Applicationsmentioning

confidence: 99%

Regulation of Bim in Health and Disease

Sionov¹,

Vlahopoulos

Granot³

2015

Oncotarget

164

124

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The BH3-only Bim protein is a major determinant for initiating the intrinsic apoptotic pathway under both physiological and pathophysiological conditions. Tight regulation of its expression and activity at the transcriptional, translational and post-translational levels together with the induction of alternatively spliced isoforms with different pro-apoptotic potential, ensure timely activation of Bim. Under physiological conditions, Bim is essential for shaping immune responses where its absence promotes autoimmunity, while too early Bim induction eliminates cytotoxic T cells prematurely, resulting in chronic inflammation and tumor progression. Enhanced Bim induction in neurons causes neurodegenerative disorders including Alzheimer's, Parkinson's and Huntington's diseases. Moreover, type I diabetes is promoted by genetically predisposed elevation of Bim in β-cells. On the contrary, cancer cells have developed mechanisms that suppress Bim expression necessary for tumor progression and metastasis. This review focuses on the intricate network regulating Bim activity and its involvement in physiological and pathophysiological processes.

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Regulatory network reconstruction reveals genes with prognostic value for chronic lymphocytic leukemia

2015

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BackgroundThe clinical course of chronic lymphocytic leukemia (CLL) is highly variable; some patients follow an indolent course, but others progress to a more advanced stage. The mutational status of rearranged immunoglobulin heavy chain variable (IGVH) genes in CLL is a feature that is widely recognized for dividing patients into groups that are related to their prognoses. However, the regulatory programs associated with the IGVH statuses are poorly understood, and markers that can precisely predict survival outcomes have yet to be identified.MethodsIn this study, (i) we reconstructed gene regulatory networks in CLL by applying an information-theoretic approach to the expression profiles of 5 cohorts. (ii) We applied master regulator analysis (MRA) to these networks to identify transcription factors (TFs) that regulate an IGVH mutational status signature. The IGVH mutational status signature was developed by searching for differentially expressed genes between the IGVH mutational statuses in numerous CLL cohorts. (iii) To evaluate the biological implication of the inferred regulators, prognostic values were determined using time to treatment (TTT) and overall survival (OS) in two different cohorts.ResultsA robust IGVH expression signature was obtained, and various TFs emerged as regulators of the signature in most of the reconstructed networks. The TF targets expression profiles exhibited significant differences with respect to survival, which allowed the definition of a reduced profile with a high value for OS. TCF7 and its targets stood out for their roles in progression.ConclusionTFs and their targets, which were obtained merely from inferred regulatory associations, have prognostic implications and reflect a regulatory context for prognosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12864-015-2189-6) contains supplementary material, which is available to authorized users.

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Differential Gene Expression Profile Associated to Apoptosis Induced by Dexamethasone in CLL Cells According to IGHV/ZAP-70 Status

Abstract: Unmutated IGHV/high ZAP-70 CLL cells exhibit better response to dexamethasone treatment, which is accompanied by a differential expression of genes involved in the glucocorticoid receptor pathway and by an increased induction of genes related to apoptosis.

Cited by 5 publications

References 49 publications

Guilty bystanders: nurse-like cells as a model of microenvironmental support for leukemic lymphocytes

Guilty bystanders: nurse-like cells as a model of microenvironmental support for leukemic lymphocytes

Regulation of Bim in Health and Disease

Regulatory network reconstruction reveals genes with prognostic value for chronic lymphocytic leukemia

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