Results of heavy-water labeling studies have challenged the notion that chronic lymphocytic leukemia (CLL) represents an accumulation of noncycling B cells. We examined leukemia cell turnover in Emu-TCL1 transgenic (TCL1-Tg) mice, which develop a CLL-like disease at 8 to 12 months of age. We found that leukemia cells in these mice not only had higher proportions of proliferating cells but also apoptotic cells than did nonleukemic lymphocytes. We crossed TCL1-Tg with BAFF-Tg mice, which express high levels of CD257. TCL1 x BAFF-Tg mice developed CLL-like disease at a significantly younger age and had more rapid disease progression and shorter survival than TCL1-Tg mice. Leukemia cells of TCL1 x BAFF-Tg mice had similar proportions of proliferating cells, but fewer proportions of dying cells, than did the CLL cells of TCL1-Tg mice. Moreover, leukemia cells from either TCL1 x BAFF-Tg or TCL1-Tg mice produced more aggressive disease when transferred into BAFF-Tg mice than into wild-type (WT) mice. Neutralization of CD257 resulted in rapid reduction in circulating leukemia cells. These results indicate that the leukemia cells of TCL1-Tg mice undergo high levels of spontaneous apoptosis that is offset by relatively high rates of leukemia cell proliferation, which might allow for acquisition of mutations that contribute to disease evolution.
"It is apparent that antigenic stimulation, autoimmunity, and inflammation contribute to the development of CLL (90). One mechanism through which these stimuli promote CLL development is induction of B cell activating factor (BAFF), a member of the TNF family, recently shown to accelerate development of CLL-like disease in mice (91). In addition, cytokines such as IL6 and interactions with bone marrow stromal cells support CLL expansion and suppress apoptosis through the expression of Bcl-2, Survivin, and Mcl-1 (92, 93). "
[Show abstract][Hide abstract] ABSTRACT: Pattern recognition receptors (PRRs) expressed on immune cells are crucial for the early detection of invading pathogens, in initiating early innate immune response and in orchestrating the adaptive immune response. PRRs are activated by specific pathogen-associated molecular patterns that are present in pathogenic microbes or nucleic acids of viruses or bacteria. However, inappropriate activation of these PRRs, such as the Toll-like receptors (TLRs), due to genetic lesions or chronic inflammation has been demonstrated to be a major cause of many hematological malignancies. Gain-of-function mutations in the TLR adaptor protein MYD88 found in 39% of the activated B cell type of diffuse large B cell lymphomas and almost 100% of Waldenström's macroglobulinemia further highlight the involvement of TLRs in these malignancies. MYD88 mutations result in the chronic activation of TLR signaling pathways, thus the constitutive activation of the transcription factor NFκB to promote cell survival and proliferation. These recent insights into TLR pathway driven malignancies warrant the need for a better understanding of TLRs in cancers and the development of novel anti-cancer therapies targeting TLRs. This review focuses on TLR function and signaling in normal or inflammatory conditions, and how mutations can hijack the TLR signaling pathways to give rise to cancer. Finally, we discuss how potential therapeutic agents could be used to restore normal responses to TLRs and have long lasting anti-tumor effects.
Frontiers in Immunology 07/2014; 5:367. DOI:10.3389/fimmu.2014.00367
"It has been proposed that repeated antigenic stimulation, autoimmunity, and inflammation are risk factors for chronic lymphocytic leukemia (CLL), the most common hematopoietic malignancy that accounts for 30% of all leukemias (Chiorazzi et al., 2005). One mechanism through which such stimuli promote CLL development is induction of B cell activating factor (BAFF), a member of the TNF family, recently shown to accelerate development of CLL-like disease in mice (Enzler et al., 2009). Cytokines (such as IL-4 and VEGF), chemokines (such as SDF-1), and interactions with bone marrow stromal cells support CLL expansion and suppress apoptosis through upregulation of Bcl-2, survivin, and MCL-1 (Granziero et al., 2001; Pedersen et al., 2002). "
[Show abstract][Hide abstract] ABSTRACT: Inflammatory responses play decisive roles at different stages of tumor development, including initiation, promotion, malignant conversion, invasion, and metastasis. Inflammation also affects immune surveillance and responses to therapy. Immune cells that infiltrate tumors engage in an extensive and dynamic crosstalk with cancer cells, and some of the molecular events that mediate this dialog have been revealed. This review outlines the principal mechanisms that govern the effects of inflammation and immunity on tumor development and discusses attractive new targets for cancer therapy and prevention.
[Show abstract][Hide abstract] ABSTRACT: Chronic lymphocytic leukaemia (CLL) is characterised by accumulation of CD5(+) monoclonal B cells in primary and secondary lymphoid tissues. Genetic defects and stimuli originating from the microenvironment concur to the selection and expansion of the malignant clone. Several lines of evidence, including molecular and functional analysis of the monoclonal immunoglobulin, support the hypothesis that stimulation through the B-cell receptor affects life and death of leukaemic cells. The microenvironment also has a critical role in the survival and accumulation of leukaemic cells within lymphoid organs where signals delivered from the surrounding cells are likely crucial in inducing proliferation. Nevertheless, several major biological issues still remain to be solved including regulation of the balance between proliferation and survival of leukaemic cells and the links between emerging gene abnormalities and microenvironment. In this context, mouse models are helpful tools in understanding disease mechanisms and in evaluating the efficacy of novel therapeutic agents.
Best practice & research. Clinical haematology 03/2010; 23(1):21-32. DOI:10.1016/j.beha.2009.12.005 · 2.12 Impact Factor
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