TCL1 transgenic mouse model as a tool for the study of therapeutic targets and microenvironment in human B-cell chronic lymphocytic leukemia

Bresin, Antonella; D’Abundo, Lucilla; Narducci, Maria Grazia; Fiorenza, Maria Teresa; Croce, Carlo M.; Negrini, Massimo; Russo, Giandomenico

doi:10.1038/cddis.2015.419

Cited by 42 publications

(32 citation statements)

References 96 publications

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“…Recently developed GEMMs use tissue specific approaches to dysregulate gene expression in specific cell types or tissues and provide temporal control of Cre‐recombinase‐mediated excision and disease onset . These endow the study of tumor initiation and provide an intact microenvironment that contains stromal and immune populations more representative of disease propagation in patients . These models endow the study of potential modifier effects resulting from multiple genetic lesions frequently encountered in patients.…”

Section: Prospective Modeling Of Leukemia In Murine Modelsmentioning

confidence: 99%

“…These models have been instrumental in the identification of the mechanisms of leukemogenesis, providing advances in understanding leukemic progression, the role of the niche, and aiding in the identification of novel therapeutic targets. Many of the referenced models have also contributed key insights into stromal remodeling, detailed below .…”

Section: Prospective Modeling Of Leukemia In Murine Modelsmentioning

confidence: 99%

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Concise Review: Adaptation of the Bone Marrow Stroma in Hematopoietic Malignancies: Current Concepts and Models

2018

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The bone marrow stroma maintains hematopoiesis and coordinately regulates regenerative responses through dynamic interactions with hematopoietic stem and progenitor cells. Recent studies indicate that stromal components in the bone marrow of leukemia patients undergo a process of successive adaptation that in turn exerts dramatic effects on the hematopoietic stem cell compartment and promotes leukemic drug resistance. Therefore, functional changes in discrete marrow stromal populations can be considered an aspect of leukemia biogenesis in that they create an aberrant, self-reinforcing microenvironment. In this review, we will describe the current understanding of the remodeling of the hematopoietic stem cell niche following invasion by leukemia cells. We place emphasis on existing evidence of how mesenchymal stem cells and their progeny facilitate neoplastic growth and describe available models and analytical techniques to understand the conversion of the niche toward disease persistence. STEM CELLS 2018;36:304-312 SIGNIFICANCE STATEMENTThere is increasing awareness that the bone marrow microenvironment is a critical contributor to therapeutic resistance and relapse progression in hematological malignancies. Experimental evidence discussed herein highlights key aspects of the stromal conversion by leukemia and the resulting aberrant signaling within the niche. This article discusses the advantages and limitations of available experimental model system and emphasizes open scientific questions and opportunities.

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Section: Prospective Modeling Of Leukemia In Murine Modelsmentioning

confidence: 99%

Section: Prospective Modeling Of Leukemia In Murine Modelsmentioning

confidence: 99%

Concise Review: Adaptation of the Bone Marrow Stroma in Hematopoietic Malignancies: Current Concepts and Models

2018

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“…To help decipher the pathogenic mechanisms of disease and evaluate the efficacy and mechanisms of action of novel therapies, researchers have developed mouse models that resemble human CLL (12,13). The Eµ-TCL1 transgenic (TCL1-tg) mouse develops a leukemia that is highly similar to the aggressive form of human CLL (14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

Anti-leukemic activity of microRNA-26a in a chronic lymphocytic leukemia mouse model

et al. 2017

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Dysregulation of microRNAs (miRNAs) plays an important role in the pathogenesis of chronic lymphocytic leukemia (CLL). The Eμ-TCL1 transgenic mouse develops a form of leukemia that is similar to the aggressive type of human B-CLL, and this valuable model has been widely used for testing novel therapeutic approaches. Here, we adopted this model to investigate the potential effects of miR-26a, miR-130an and antimiR-155 in CLL therapy. Improved delivery of miRNA molecules into CLL cells was obtained by developing a novel system based on lipid nanoparticles conjugated with an anti-CD38 monoclonal antibody. This methodology has proven to be highly effective in delivering miRNA molecules into leukemic cells. Short- and long-term experiments showed that miR-26a, miR-130a and anti-miR-155 increased apoptosis after in vitro and in vivo treatment. Of this miRNA panel, miR-26a was the most effective in reducing leukemic cell expansion. Following long-term treatment, apoptosis was readily detectable by analyzing cleavage of PARP and caspase-7. These effects could be directly attributed to miR-26a, as confirmed by significant downregulation of its proven targets, namely cyclin-dependent kinase 6 and Mcl1. The results of this study are relevant to two distinct areas. The first is related to the design of a technical strategy and to the selection of CD38 as a molecular target on CLL cells, both consenting efficient and specific intracellular transfer of miRNA. The original scientific finding inferred from the above approach is that miR-26a can elicit in vivo anti-leukemic activities mediated by increased apoptosis.

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“…Activation of the PI3K/AKT and MEK/ERK pathways is common in different types of cancer (20)(21)(22)(23) and, in solid tumors, it is often associated with poor prognosis (24). AKT and ERK play crucial roles in cell proliferation, metastasis, angiogenesis, and drug response.…”

Section: Discussionmentioning

confidence: 99%

Effects of PHA-665752 and vemurafenib combination treatment on inï¿½vitro and murine xenograft growth of human colorectal cancer cells with BRAFV600E mutations

Zhi

et al. 2018

Oncol Lett

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Abstract. It remains unknown whether blockade of B-Raf proto-oncogene, serine/threonine kinase (BRAF) V600E signaling and MET proto-oncogene, receptor tyrosine kinase (c-Met) signaling is effective in suppressing the growth of human colorectal cancer (CRC) cells. The present study investigated the effects of the vemurafenib alone and in combination with c-Met inhibitor PHA-665752 on the growth of human CRC cells in vitro and in mouse xenografts. HT-29 and RKO CRC cell lines with BRAF V600E mutations and mice bearing HT-29 xenografts were treated with vemurafenib in the absence or presence of PHA-665752. Cell viability and cycle phase were respectively examined by using the MTT and flow cytometry assay. Immunohistochemistry was conducted to detect the protein expression levels of hepatocyte growth factor (HGF), phosphorylated (p)-c-Met, p-AKT serine/threonine kinase (AKT) and p-extracellular signal-regulated kinase (p-ERK). The MTT assay demonstrated that the growth of RKO and HT-29 cells was inhibited by PHA-665752 in a time-and dose-dependent manner (P<0.05), however no significant suppressive effects were observed with vemurafenib. Relative to the PHA-665752 or vemurafenib stand-alone treatment groups, the combination of PHA-665752 and vemurafenib had a significant inhibitory effect on the proliferation of CRC cell lines (P<0.05). The mean tumor volume in mice treated with vemurafenib in combination with PHA-665752 was significantly smaller compared with those treated with only vemurafenib or PHA-665752 (P<0.05). Flow cytometry assay revealed that the G0/G1 phase frequency was significantly increased in the combination group compared with any other treatment groups (P<0.05). Immunohistochemistry demonstrated that vemurafenib in combination with PHA-665752 effectively induced the expression of p-c-Met, p-AKT and p-ERK, however had no effect on HGF. IntroductionColorectal cancer (CRC) is one of the principal causes of cancer worldwide (1). Unfortunately, even if a 5-year survival prognosis can be given to 90% of patients in the early stages, disappointing treatment outcomes are recorded in subjects with extensive local invasion or distant metastases. Generally, their 5-year survival rate is less than 15% (2) and, even if suitable for receiving adjuvant chemotherapy, disease-related deaths remain stubbornly high.A recent steady stream of important breakthroughs has dramatically improved our understanding of CRC. One such discovery identified the BRAF mutation as common in metastatic CRC patients, especially those with a right-side colon cancer and a poorly differentiated tumor (3). Vemurafenib is a potent and selective inhibitor of mutated BRAF. Chapman et al (4) revealed that vemurafenib achieved 40% response rates in melanoma with a BRAF mutation. However, unlike melanoma, the effect of vemurafenib in CRC patients with a BRAF mutation is often negligible, resulting in a clinical response in only 5% of patients (5). This discrepancy of outcomes suggests that different cancer types may present important variat...

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TCL1 transgenic mouse model as a tool for the study of therapeutic targets and microenvironment in human B-cell chronic lymphocytic leukemia

Cited by 42 publications

References 96 publications

Concise Review: Adaptation of the Bone Marrow Stroma in Hematopoietic Malignancies: Current Concepts and Models

Concise Review: Adaptation of the Bone Marrow Stroma in Hematopoietic Malignancies: Current Concepts and Models

Anti-leukemic activity of microRNA-26a in a chronic lymphocytic leukemia mouse model

Effects of PHA-665752 and vemurafenib combination treatment on inï¿½vitro and murine xenograft growth of human colorectal cancer cells with BRAFV600E mutations

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