Article

Chronic lymphocytic leukemia of E mu-TCL1 transgenic mice undergoes rapid cell turnover that can be offset by extrinsic CD257 to accelerate disease progression

Moores Cancer Center, Department of Medicine, School of Medicine, University of California San Diego, La Jolla, CA, USA.
Blood (Impact Factor: 10.43). 09/2009; 114(20):4469-76. DOI: 10.1182/blood-2009-06-230169
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
113 Views
  • Source
    [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.
    Cell 03/2010; 140(6):883-99. DOI:10.1016/j.cell.2010.01.025 · 33.12 Impact Factor
  • [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 · 2.55 Impact Factor
  • Blood 05/2010; 115(19):3858-9. DOI:10.1182/blood-2010-02-267278 · 10.43 Impact Factor