Molecular pathogenesis of chronic lymphocytic leukemia: factors and signaling pathways regulating cell growth and survival

Meinhardt, Gerold; Wendtner, Clemens-M.; Hallek, Michael

doi:10.1007/s001090050351

Cited by 73 publications

(50 citation statements)

References 134 publications

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“…Polymorphisms of the βAR genes have been associated with diseases, including asthma (Chung et al 2011;Johnson 2001), obesity (Martinez et al 2003), and cancer (Wang et al 2006). In cancer, they are associated with cell proliferation and apoptosis (Meinhardt et al 1999;Sastry et al 2007), chemotaxis and metastasis (Entschladen et al 2002;Lang et al 2004;Shang et al 2009), and tumor growth (Shang et al 2009). Consistent with these results, βARs are also localized in epithelium, endothelium, nerve axons/processes, and mast cells (Chung et al 2011;Daly and McGrath 2011).…”

Section: Discussionmentioning

confidence: 99%

β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice

Spindler

Mote

et al. 2013

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Chronic treatment with β-adrenergic receptor (βAR) agonists increases mortality and morbidity while βAR antagonists (β-blockers) decrease allcause mortality for those at risk of cardiac disease. Levels of sympathetic nervous system βAR agonists and βAR activity increase with age, and this increase may hasten the development of age-related mortality.Here, we show that β-blockers extend the life span of healthy metazoans. The β-blockers metoprolol and nebivolol, administered in food daily beginning at 12 months of age, significantly increase the mean and median life span of isocalorically fed, male C3B6F1 mice, by 10 and 6.4 %, respectively (P< 0.05). Neither drug affected the weight or food intake of the mice, indicating that induced CR is not responsible for these effects, and that energy absorption and utilization are not altered by the drugs. Both β-blockers were investigated to control for their idiosyncratic, off-target effects. Metoprolol and nebivolol extended Drosophila life span, without affecting food intake or locomotion. Thus, βAR antagonists are capable of directly extending the life span of two widely divergent metazoans, suggesting that these effects are phylogenetically highly conserved. Thus, long-term use of β-blockers, which are generally well-tolerated, may enhance the longevity of healthy humans.

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Section: Discussionmentioning

confidence: 99%

β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice

Spindler

Mote

et al. 2013

AGE

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“…The NZB malignant B-1 expansion has many similarities to the human disease CLL (reviewed in Chiorazzi and Ferrarini 26 ), which is also an ageassociated malignant B-cell expansion of self-reactive, 27 often anti-RBC-specific, 28 CD5 þ B-1 clones, which display defects in the induction of programmed cell death 29 and frequently have chromosomal instability. 30,31 Abnormal surface expression of Bcell markers has been found in CLL, including decreased B220 expression.…”

Section: Discussionmentioning

confidence: 99%

Studies in NZB IL-10 knockout mice of the requirement of IL-10 for progression of B-cell lymphoma

et al. 2004

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NZB mice develop an age-related malignant expansion of a subset of B cells, B-1 cells, with autocrine production of IL-10. IL-10, a pleiotropic cytokine with anti-inflammatory properties, is a potent growth and survival factor for malignant B cells. To further examine the in vivo requirement for IL-10 in the development and expansion of malignant B-1 clones in NZB mice, we developed a strain of homozygous IL-10 knockout (KO) mice on an NZB background. The NZB IL-10 KO mice develop peritoneal B-1 cells with approximately the same frequency as heterozygous and wild-type littermates. In contrast, the development of malignant B-1 cells in the peripheral blood and spleen, observed in wild-type NZB, rarely occurred in the NZB IL-10 KO. Phenotypic analysis of surface marker expression in splenic B cells indicated that, in contrast to the NZB with malignant B-1 splenic lymphoma, the surface marker expression of NZB IL-10 KO splenic B cells indicated that the majority of the B cells were typical B-2 cells. In the absence of IL-10, spontaneously activated B cells and antiapoptotic gene expression were reduced and lymphoma incidence was decreased. These results indicate that IL-10 is a critical factor for the progression of this B-cell malignant disease.

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“…B-cell chronic lymphocytic leukaemia (B-CLL) is a lymphoproliferative disorder characterized by the expansion and accumulation of monoclonal CD5 1 B lymphocytes (Foon et al, 1990;Kipps, 1998;Meinhardt et al, 1999). In half of the cases, somatic hypermutations have been detected within the tumour cell-derived immunoglobulin V gene segments region, indicating a post-germinal centre cell origin (Fais et al, 1998;Hamblin et al, 1999;Naylor & Capra, 1999).…”

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confidence: 99%

Autologous T lymphocytes may specifically recognize leukaemic B cells in patients with chronic lymphocytic leukaemia

et al. 2000

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Summary. This study analysed a naturally occurring specific cellular immunity against tumour cells in chronic lymphocytic leukaemia (CLL) patients. Five out of eight patients had blood T lymphocytes able to recognize spontaneously and specifically the autologous tumour B cells (proliferation assay). In these five patients, detection of cytokines by realtime reverse transcription polymerase chain reaction (RT-PCR) revealed that granulocyte±macrophage colony-stimulating factor (GM-CSF) was the most abundant cytokine gene expressed by the T cells that recognized the autologous tumour B cells. Other activated cytokine genes were ginterferon (IFN), interleukin (IL)-2 and tumour necrosis factor (TNF)-a, but not IL-4. This profile suggests a type 1 anti-B-CLL T-cell response. CD80 and CD54 were relatively downregulated on the native tumour B cells compared with control normal B cells. Upregulation of CD80 on the leukaemic cells was mandatory for the induction of such a specific T-cell response. CD80 and CD54 monoclonal antibodies inhibited the specific T-cell DNA synthesis proliferation. The proliferative T-cell response was either MHC class I or class II restricted (inhibition by monoclonal antibodies). The specific cytokine gene expression could be found in isolated CD4, as well as CD8, T-cell subsets. This study demonstrated the presence of a potential natural specific CD4, as well as a CD8 type 1 T-cell immunity against the leukaemic CLL tumour B cells in CLL. A further detailed analysis of the spontaneous anti-CLL T-cell immunity is warranted that may facilitate the development of effective anti-tumour vaccines in CLL.

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Molecular pathogenesis of chronic lymphocytic leukemia: factors and signaling pathways regulating cell growth and survival

Cited by 73 publications

References 134 publications

β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice

β1-Adrenergic receptor blockade extends the life span of Drosophila and long-lived mice

Studies in NZB IL-10 knockout mice of the requirement of IL-10 for progression of B-cell lymphoma

Autologous T lymphocytes may specifically recognize leukaemic B cells in patients with chronic lymphocytic leukaemia

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