A novel adoptive transfer model of chronic lymphocytic leukemia suggests a key role for T lymphocytes in the disease

The Feinstein Institute for Medical Research, North Shore-LIJ Health System, 350 Community Drive, Manhasset, NY 11030, USA.
Blood (Impact Factor: 10.45). 03/2011; 117(20):5463-72. DOI: 10.1182/blood-2010-12-324210
Source: PubMed

ABSTRACT Chronic lymphocytic leukemia (CLL) is an incurable adult disease of unknown etiology. Understanding the biology of CLL cells, particularly cell maturation and growth in vivo, has been impeded by lack of a reproducible adoptive transfer model. We report a simple, reproducible system in which primary CLL cells proliferate in nonobese diabetes/severe combined immunodeficiency/γc(null) mice under the influence of activated CLL-derived T lymphocytes. By co-transferring autologous T lymphocytes, activated in vivo by alloantigens, the survival and growth of primary CFSE-labeled CLL cells in vivo is achieved and quantified. Using this approach, we have identified key roles for CD4(+) T cells in CLL expansion, a direct link between CD38 expression by leukemic B cells and their activation, and support for CLL cells preferentially proliferating in secondary lymphoid tissues. The model should simplify analyzing kinetics of CLL cells in vivo, deciphering involvement of nonleukemic elements and nongenetic factors promoting CLL cell growth, identifying and characterizing potential leukemic stem cells, and permitting preclinical studies of novel therapeutics. Because autologous activated T lymphocytes are 2-edged swords, generating unwanted graph-versus-host and possibly autologous antitumor reactions, the model may also facilitate analyses of T-cell populations involved in immune surveillance relevant to hematopoietic transplantation and tumor cytoxicity.

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Available from: Hakan Mellstedt, Dec 16, 2013
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    • "Confirming in vitro studies, we provide clear evidence that nanoliposomal C6-ceramide demonstrated in vivo efficacy via tumor growth inhibition in a murine xenograft model of CLL. We are aware of a recently described mouse model for CLL generated by co-injection of primary human CLL cells and T cells into NOD/ SCID mice, but have chosen to focus our studies on the mouse xenograft model because we can obtain tissue for ex vivo Western analysis of GAPDH protein levels [48]. In our in vivo studies we observed that treatment with nanoliposomal C6-ceramide effectively decreased tumor burden without systemic side effects. "
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    ABSTRACT: Ceramide is a sphingolipid metabolite that induces cancer cell death. When C6-ceramide is encapsulated in a nanoliposome bilayer formulation, cell death is selectively induced in tumor models. However, the mechanism underlying this selectivity is unknown. As most tumors exhibit a preferential switch to glycolysis, as described in the "Warburg effect", we hypothesize that ceramide nanoliposomes selectively target this glycolytic pathway in cancer. We utilize chronic lymphocytic leukemia (CLL) as a cancer model, which has an increased dependency on glycolysis. In CLL cells, we demonstrate that C6-ceramide nanoliposomes, but not control nanoliposomes, induce caspase 3/7-independent necrotic cell death. Nanoliposomal ceramide inhibits both the RNA and protein expression of GAPDH, an enzyme in the glycolytic pathway, which is overexpressed in CLL. To confirm that ceramide targets GAPDH, we demonstrate that downregulation of GAPDH potentiates the decrease in ATP after ceramide treatment and exogenous pyruvate treatment as well as GAPDH overexpression partially rescues ceramide-induced necrosis. Finally, an in vivo murine model of CLL shows that nanoliposomal C6-ceramide treatment elicits tumor regression, concomitant with GAPDH downregulation. We conclude that selective inhibition of the glycolytic pathway in CLL cells with nanoliposomal C6-ceramide could potentially be an effective therapy for leukemia by targeting the Warburg effect.
    PLoS ONE 12/2013; 8(12):e84648. DOI:10.1371/journal.pone.0084648 · 3.23 Impact Factor
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    • "Although such a role for B cells has been demonstrated neither in CLL nor in paraneoplastic syndromes, it has been known for long time that quantitative and qualitative abnormalities of T cells are present in B-CLL [11]. Recently, a murine model suggesting a crucial role of T cells in CLL has been reported [12]. "
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    ABSTRACT: Limbic encephalitis is an inflammatory disease of the central nervous system characterized by diverse neurologic symptoms including mnestic disturbances, hallucinations, and seizures as well as behavioral symptoms like depression, personality changes, and acute confusional states resembling dementia. Several antibodies have been described in the pathogenesis of limbic encephalitis. It is often a paraneoplastic syndrome associated with small cell lung cancer, breast cancer, or Hodgkin's lymphoma among others. Here, we report a patient with B-cell chronic lymphocytic leukemia (B-CLL), presenting with otherwise unexplained neurologic symptoms consistent with limbic encephalitis. Despite intensive diagnostic procedures, no causing agent could be identified. Pleocytosis consisting of T cells was detected in the cerebrospinal fluid (CSF). We initiated anti-B-cell therapy with Rituximab for B-CLL with quick and durable resolution of symptoms. We speculate that disruption of interaction between autoreactive T and malignant B cells is responsible for the therapeutic effect of Rituximab.
    08/2013; 2013:958704. DOI:10.1155/2013/958704
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    • "Nevertheless, predominant T cell engraftment after transplantation of MNCs from patients with malignant myeloid diseases was apparently also observed by others, as T cell depletion is described in the ‘material and method’ section of some studies [53]–[56]. Furthermore, lethal xGvHD was also observed when transplanting human MNCs to achieve engraftment of chronic lymphocytic leukemia (CLL) suggesting a similar phenomenon for lymphoid diseases [57]. Nevertheless, T cell expansion after transplantation of AML-MNCs or MNCs from patients with low-risk myelodysplastic syndrome (MDS) has only been incompletely described so far [54]–[56]. "
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    ABSTRACT: Human cells from acute myeloid leukemia (AML) patients are frequently transplanted into immune-compromised mouse strains to provide an in vivo environment for studies on the biology of the disease. Since frequencies of leukemia re-initiating cells are low and a unique cell surface phenotype that includes all tumor re-initiating activity remains unknown, the underlying mechanisms leading to limitations in the xenotransplantation assay need to be understood and overcome to obtain robust engraftment of AML-containing samples. We report here that in the NSG xenotransplantation assay, the large majority of mononucleated cells from patients with AML fail to establish a reproducible myeloid engraftment despite high donor chimerism. Instead, donor-derived cells mainly consist of polyclonal disease-unrelated expanded co-transplanted human T lymphocytes that induce xenogeneic graft versus host disease and mask the engraftment of human AML in mice. Engraftment of mainly myeloid cell types can be enforced by the prevention of T cell expansion through the depletion of lymphocytes from the graft prior transplantation.
    PLoS ONE 04/2013; 8(4):e60680. DOI:10.1371/journal.pone.0060680 · 3.23 Impact Factor
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