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

Simonetti, Giorgia; Bertilaccio, Maria Teresa Sabrina; Ghia, Paolo; Klein, Ulf

doi:10.1182/blood-2014-05-577122

Cited by 73 publications

(66 citation statements)

References 123 publications

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“…Modeling of CLL development in mice will be crucial to decipher the pathogenic role of recurrent genomic aberrations. Several mouse models have been developed which to some extent recapitulate the human disease [156]. The differences between man and mouse, particularly with respect to lymphoid differentiation, make it difficult to interpret.…”

Section: Discussionmentioning

confidence: 99%

Chronic lymphocytic leukemia: Time to go past genomics?

2016

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Recent advances in massively parallel sequencing technologies have provided a detailed picture of the mutational landscape in CLL and underscored the vast degree of interpatient and intratumor heterogeneities. These studies have led to the characterization of novel putative driver genes and recurrently affected biological pathways, and to the modeling of CLL clonal evolution. We herein review selected aspects including recent advances in the biology of CLL and present cellular and biological processes involved in the development of CLL and potentially other mature B-cell lymphoproliferative neoplasms.

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Section: Discussionmentioning

confidence: 99%

Chronic lymphocytic leukemia: Time to go past genomics?

2016

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“…61 Analysis of transgenic mouse models overexpressing APRIL or BAFF confirmed the importance of microenvironmental interactions in CLL development as these models developed aggressive forms of CLL with increased survival of CLL cells. 62 By secreting cytokines and chemokines, CAFs induce recruitment and retention of macrophages and other immune effector cells. 38 Of interest, CCL2 and CXCL16 induced by CLL exosomes are important chemoattractants for macrophages and T cells, respectively.…”

Section: Cll Exosomes Induce Caf Formation 1113mentioning

confidence: 99%

Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts

Paggetti

Haderk

Seiffert

et al. 2015

Blood

395

397

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Luxembourg Key Points• CLL-derived exosomes are internalized by stromal cells, deliver functional microRNA and proteins, and activate key signaling pathways.• Stromal cells exposed to CLLderived exosomes demonstrate a CAF-like phenotype and secrete factors promoting CLL cell survival.Exosomes derived from solid tumor cells are involved in immune suppression, angiogenesis, and metastasis, but the role of leukemia-derived exosomes has been less investigated. The pathogenesis of chronic lymphocytic leukemia (CLL) is stringently associated with a tumorsupportive microenvironment and a dysfunctional immune system. Here, we explore the role of CLL-derived exosomes in the cellular and molecular mechanisms by which malignant cells create this favorable surrounding. We show that CLL-derived exosomes are actively incorporated by endothelial and mesenchymal stem cells ex vivo and in vivo and that the transfer of exosomal protein and microRNA induces an inflammatory phenotype in the target cells, which resembles the phenotype of cancer-associated fibroblasts (CAFs). As a result, stromal cells show enhanced proliferation, migration, and secretion of inflammatory cytokines, contributing to a tumor-supportive microenvironment. Exosome uptake by endothelial cells increased angiogenesis ex vivo and in vivo, and coinjection of CLL-derived exosomes and CLL cells promoted tumor growth in immunodeficient mice. Finally, we detected a-smooth actin-positive stromal cells in lymph nodes of CLL patients. These findings demonstrate that CLL-derived exosomes actively promote disease progression by modulating several functions of surrounding stromal cells that acquire features of cancer-associated fibroblasts. (Blood. 2015;126(9):1106-1117

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“…However, since the signaling pathways activated and additional oncogenic hits are very similar to the human disease, the model has proven its value in CLL research [55]. …”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Constitutive Kit activity triggers B-cell acute lymphoblastic leukemia-like disease in mice

Weidemann

Behrendt

Schoedel

et al. 2017

Experimental Hematology

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Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and is of pro-or pre-B cell origin in most cases. The receptor tyrosine kinase KIT is expressed by hematopoietic stem and precursor cells. Gain-of-function mutations of KIT cause systemic mastocytosis, which is characterized by abnormal accumulations of mast cells. We previously reported a mouse model of mastocytosis based on conditional expression of a constitutively active Kit protein. Half of these animals developed leukemic disease of B lineage origin. Herein, we report that this condition bears striking similarities to human B-ALL. The immuno-phenotype of the leukemic cells was compatible with a pro-B cell origin, as was the finding of immunoglobulin heavy chain gene rearrangements in all cases, whereas light chain loci were mostly not rearranged. Leukemogenesis was independent of pre-B cell receptor expression.Primary leukemic cells and permanent cell lines derived from these were serially transplantable and rapidly killed the recipients. In few animals, the leukemia was of T cell origin with abnormal CD4/8 double positive T cell precursors dominating in the circulation. In summary, we report a novel ALL mouse model that may prove useful for in vivo drug testing and identification of novel oncogenic mutations and principles.

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

Cited by 73 publications

References 123 publications

Chronic lymphocytic leukemia: Time to go past genomics?

Chronic lymphocytic leukemia: Time to go past genomics?

Exosomes released by chronic lymphocytic leukemia cells induce the transition of stromal cells into cancer-associated fibroblasts

Constitutive Kit activity triggers B-cell acute lymphoblastic leukemia-like disease in mice

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