Role of CTLA4 in the Proliferation and Survival of Chronic Lymphocytic Leukemia

Mittal, Amit; Chaturvedi, Nagendra K.; Rohlfsen, Rae A.; Gupta, P. C. Sen; Joshi, Avadhut D.; Hegde, Ganapati V.; Bociek, R. Gregory; Joshi, Shantaram S.

doi:10.1371/journal.pone.0070352

Cited by 42 publications

(47 citation statements)

References 52 publications

(60 reference statements)

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“…In contrast, Mittal and colleagues described that CTLA-4 expression on CLL cells is generally associated with good clinical outcome and that the presence of a polymorphism of CTLA-4 is correlated to increased risk and advanced Rai stages in CLL [49]. They showed that in vitro CTLA-4 down-modulation increases the proliferation rate of leukemic cells and upregulates surface expression of CD38, a well-known marker of high-risk CLL, together with the expression of STAT1, NFATC2 and c-Myc, which represent downstream molecules of the B-cell proliferation/survival signaling pathway [50].…”

Section: Cytotoxic T Lymphocyte Antigen-4 (Ctla-4)/b7mentioning

confidence: 99%

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

Arruga

Gyau

Iannello

et al. 2020

IJMS

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Representing the major cause of morbidity and mortality for chronic lymphocytic leukemia (CLL) patients, immunosuppression is a common feature of the disease. Effectors of the innate and the adaptive immune response show marked dysfunction and skewing towards the generation of a tolerant environment that favors disease expansion. Major deregulations are found in the T lymphocyte compartment, with inhibition of CD8+ cytotoxic and CD4+ activated effector T cells, replaced by exhausted and more tolerogenic subsets. Likewise, differentiation of monocytes towards a suppressive M2-like phenotype is induced at the expense of pro-inflammatory sub-populations. Thanks to their B-regulatory phenotype, leukemic cells play a central role in driving immunosuppression, progressively inhibiting immune responses. A number of signaling cascades triggered by soluble mediators and cell–cell contacts contribute to immunomodulation in CLL, fostered also by local environmental conditions, such as hypoxia and derived metabolic acidosis. Specifically, molecular pathways modulating T-cell activity in CLL, spanning from the best known cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death 1 (PD-1) to the emerging T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibition motif domains (TIGIT)/CD155 axes, are attracting increasing research interest and therapeutic relevance also in the CLL field. On the other hand, in the microenvironment, the B cell receptor (BCR), which is undoubtedly the master regulator of leukemic cell behavior, plays an important role in orchestrating immune responses, as well. Lastly, local conditions of hypoxia, typical of the lymphoid niche, have major effects both on CLL cells and on non-leukemic immune cells, partly mediated through adenosine signaling, for which novel specific inhibitors are currently under development. In summary, this review will provide an overview of the molecular and microenvironmental mechanisms that modify innate and adaptive immune responses of CLL patients, focusing attention on those that may have therapeutic implications.

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Section: Cytotoxic T Lymphocyte Antigen-4 (Ctla-4)/b7mentioning

confidence: 99%

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

Arruga

Gyau

Iannello

et al. 2020

IJMS

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“…idenced low proliferative index, and higher Ki-67 expression was identified in samples from patients with advanced clinical stage or after cytokine stimulation [16][17][18][19][20][21][22] . Similar results were obtained with an in vitro proliferation study of MCL cells 23 .…”

Section: Resultsmentioning

confidence: 99%

Ki-67 expression in mature B-cell neoplasms: a flow cytometry study

Marcondes

Fernandes²,

Faulhaber

2018

Rev. Assoc. Med. Bras.

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SUMMARY OBJECTIVE: Ki-67 is a nuclear protein associated with cellular proliferation in normal or leukemic conditions that can help identify more aggressive diseases and is usually evaluated with immunohistochemistry. The aim of this was to assess Ki-67 expression on mature B-cell neoplasms samples with flow cytometry immunophenotyping. METHOD: After surface staining with CD19 and CD45, intracellular staining for Ki-67 was performed in leukemic mature B-cells. Ki-67 expression was evaluated with flow cytometry. RESULTS: Ki-67 expression was higher in mantle cell lymphoma, Burkitt lymphoma, and diffuse large B-cell lymphoma cases. It was also associated with CD38 mean fluorescence intensity. CONCLUSIONS: Ki-67 expression evaluated by flow cytometry can be a useful tool in the diagnosis of mature B-cell neoplasms. More studies are needed to validate Ki-67 assessment with flow cytometry immunophenotyping.

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“…Literature mining analysis significantly associated it with apoptosis and cell-proliferation. CTLA4 has been reported to regulate key genes involved in carcinogenesis like STAT1, NFATC2, c-Fos, c-Myc, and/or Bcl-2 [39] . Literature mining analysis and mining of TTD have identified CTLA4 as a therapeutic marker for various cancers.…”

Section: Resultsmentioning

confidence: 99%

Potential Therapeutic Targets for Oral Cancer: ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF, CD70

2014

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In India, oral cancer has consistently ranked among top three causes of cancer-related deaths, and it has emerged as a top cause for the cancer-related deaths among men. Lack of effective therapeutic options is one of the main challenges in clinical management of oral cancer patients. We interrogated large pool of samples from oral cancer gene expression studies to identify potential therapeutic targets that are involved in multiple cancer hallmark events. Therapeutic strategies directed towards such targets can be expected to effectively control cancer cells. Datasets from different gene expression studies were integrated by removing batch-effects and was used for downstream analyses, including differential expression analysis. Dependency network analysis was done to identify genes that undergo marked topological changes in oral cancer samples when compared with control samples. Causal reasoning analysis was carried out to identify significant hypotheses, which can explain gene expression profiles observed in oral cancer samples. Text-mining based approach was used to detect cancer hallmarks associated with genes significantly expressed in oral cancer. In all, 2365 genes were detected to be differentially expressed genes, which includes some of the highly differentially expressed genes like matrix metalloproteinases (MMP-1/3/10/13), chemokine (C-X-C motif) ligands (IL8, CXCL-10/-11), PTHLH, SERPINE1, NELL2, S100A7A, MAL, CRNN, TGM3, CLCA4, keratins (KRT-3/4/13/76/78), SERPINB11 and serine peptidase inhibitors (SPINK-5/7). XIST, TCEAL2, NRAS and FGFR2 are some of the important genes detected by dependency and causal network analysis. Literature mining analysis annotated 1014 genes, out of which 841 genes were statistically significantly annotated. The integration of output of various analyses, resulted in the list of potential therapeutic targets for oral cancer, which included targets such as ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF and CD70.

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Role of CTLA4 in the Proliferation and Survival of Chronic Lymphocytic Leukemia

Cited by 42 publications

References 52 publications

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

Immune Response Dysfunction in Chronic Lymphocytic Leukemia: Dissecting Molecular Mechanisms and Microenvironmental Conditions

Ki-67 expression in mature B-cell neoplasms: a flow cytometry study

Potential Therapeutic Targets for Oral Cancer: ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF, CD70

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