Xenograft models of chronic lymphocytic leukemia: problems, pitfalls and future directions

Bertilaccio, Maria Teresa Sabrina; Scielzo, Cristina; Simonetti, Giorgia; Hacken, Elisa ten; Apollonio, Benedetta; Caligaris-Cappio, Federico

doi:10.1038/leu.2012.268

Cited by 40 publications

(35 citation statements)

References 64 publications

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“…Xenograftment of either primary CLL cells or cells lines has been reviewed in Bertilaccio, et al and Chen et al 74, 91 . Supplementary to xenograft models utilizing primary CLL cells, Bertilaccio et al developed a xenograft model using a well characterized human CLL like cell line (MEC1) 92 .…”

Section: Pre-clinical Modeling In Vivomentioning

confidence: 99%

Preclinical modeling of novel therapeutics in chronic lymphocytic leukemia: the tools of the trade

Herman

Wiestner

2016

Seminars in Oncology

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In the last decade our understanding of chronic lymphocytic leukemia (CLL) biology and pathogenesis has increased substantially. These insights have led to the development of several new agents with novel mechanisms of action prompting a change in therapeutic approaches from chemotherapy based treatments to targeted therapies. Multiple pre-clinical models for drug development in CLL are available; however, with the advent of these targeted agents, it is becoming clear that not all models and surrogate readouts of efficacy are appropriate for all drugs. In this review we discuss in vitro and in vivo pre-clinical models, with a particular focus on the benefits and possible pitfalls of different model systems in the evaluation of novel therapeutics for the treatment of CLL.

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Section: Pre-clinical Modeling In Vivomentioning

confidence: 99%

Preclinical modeling of novel therapeutics in chronic lymphocytic leukemia: the tools of the trade

Herman

Wiestner

2016

Seminars in Oncology

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“…34,84,87,[90][91][92][93][94][95][96][97][98][99] Generally, transplanted animals developed a frank leukemia within a few weeks or months. Together with xenograft models of CLL, 100 such transfer experiments represent reproducible systems for the elucidation of the efficacy and mechanism of action of novel therapies. As such, preclinical studies with Em-TCL1 mice were instrumental in understanding the pathogenic relevance of molecular targets in disease biology (supplemental Table 2), as summarized in the following.…”

Section: Em-tcl1 Transgenic Mouse Model As a Preclinical Model For Nomentioning

confidence: 99%

Mouse models in the study of chronic lymphocytic leukemia pathogenesis and therapy

Simonetti

Bertilaccio

Ghia

et al. 2014

Blood

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Mouse models that recapitulate human malignancy are valuable tools for the elucidation of the underlying pathogenetic mechanisms and for preclinical studies. Several genetically engineered mouse models have been generated, either mimicking genetic aberrations or deregulated gene expression in chronic lymphocytic leukemia (CLL). The usefulness of such models in the study of the human disease may potentially be hampered by species-specific biological differences in the target cell of the oncogenic transformation. Specifically, do the genetic lesions or the deregulated expression of leukemia-associated genes faithfully recapitulate the spectrum of lymphoproliferations in humans? Do the CLL-like lymphoproliferations in the mouse have the phenotypic, histological, genetic, and clinical features of the human disease? Here we compare the various CLL mouse models with regard to disease phenotype, penetrance, and severity. We discuss similarities and differences of the murine lymphoproliferations compared with human CLL. We propose that the Eμ-TCL1 transgenic and 13q14-deletion models that have been comprehensively studied at the levels of leukemia phenotype, antigen-receptor repertoire, and disease course show close resemblance to the human disease. We conclude that modeling CLL-associated genetic dysregulations in mice can provide important insights into the molecular mechanisms of disease pathogenesis and generate valuable tools for the development of novel therapies.

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“…Therefore, with the aim of studying the specific contribution of ZAP-70 protein to the crosstalk between malignant B-cells and the microenvironment, we stably transfected malignant B-cells with ZAP-70 protein and studied the phenotypic effects. Since the establishment of a CLL cell line is still an unsolved issue (reviewed in ref [31]) we used a Burkitt's lymphoma cell line as a model of malignant mature B-lymphocyte, as previously done in several reports [16], [32]. Using this model, we previously described the direct role of ZAP-70 protein in enhancing response to the BCR and to CCR7 stimulation [16].…”

Section: Discussionmentioning

confidence: 99%

ZAP-70 Promotes the Infiltration of Malignant B-Lymphocytes into the Bone Marrow by Enhancing Signaling and Migration after CXCR4 Stimulation

et al. 2013

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ZAP-70 in chronic lymphocytic leukemia (CLL) is associated with enhanced response to microenvironmental stimuli. We analyzed the functional consequences of ZAP-70 ectopic expression in malignant B-cells in a xenograft mouse model of disseminated B-cell leukemia. Mice injected with B-cells expressing ZAP-70 showed a prominently higher infiltration of the bone marrow. In vitro analysis of the response of malignant B-cells to CXCL12, the main attracting chemokine regulating trafficking of lymphocytes to the bone marrow, or to bone marrow stromal cells, revealed that ZAP-70 induces an increased response in terms of signaling and migration. These effects are probably mediated by direct participation of ZAP-70 in CXCL12-CXCR4 signaling since CXCR4 stimulation led to activation of ZAP-70 and downstream signaling pathways, such as MAPK and Akt, whereas ZAP-70 did not alter the expression of the CXCR4 receptor. In addition, subclones of primary CLL cells with high expression of ZAP-70 also showed increased migrative capacity toward CXCL12. Neutralization of CXCR4 with a monoclonal antibody resulted in impaired in vitro responses to CXCL12 and bone marrow stromal cells. We conclude that ZAP-70 enhances the migration of malignant B-cells into the supportive microenvironment found in the bone marrow mainly by enhancing signaling and migration after CXCR4 stimulation.

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Xenograft models of chronic lymphocytic leukemia: problems, pitfalls and future directions

Cited by 40 publications

References 64 publications

Preclinical modeling of novel therapeutics in chronic lymphocytic leukemia: the tools of the trade

Preclinical modeling of novel therapeutics in chronic lymphocytic leukemia: the tools of the trade

Mouse models in the study of chronic lymphocytic leukemia pathogenesis and therapy

ZAP-70 Promotes the Infiltration of Malignant B-Lymphocytes into the Bone Marrow by Enhancing Signaling and Migration after CXCR4 Stimulation

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