The Peripheral T-Cell Lymphomas. Группа авторов
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4 Animal Models of T‐cell Lymphoma
Keiichiro Hattori1, Raksha Shrestha2, Tatsuhiro Sakamoto1,2, Manabu Kusakabe1,2 and Mamiko Sakata‐Yanagimoto1,2
1Department of Hematology, Faculty of Medicine, University of Tsukuba Hospital, Tsukuba, Japan
2Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Japan
TAKE HOME MESSAGES
Mouse models of T‐cell lymphomas have been established based on the analysis of mutational profiles or gene/protein expression profiles of human samples.
Patient‐derived xenograft models of T‐cell lymphomas have been also generated as potential preclinical tools for translational research.
Mouse models have helped to unveil the pathogenesis and signaling pathways in T‐cell lymphomas.
Mouse models provide tools to achieve higher rates of successful translation of basic research to clinical trials.
Introduction
Peripheral T‐cell lymphomas (PTCL) are a heterogeneous group of blood cancers with varying pathological and clinical features. Standard chemotherapy approaches for most PTCL are not yet well established, with the exception of anaplastic lymphoma kinase positive (ALK+) anaplastic large‐cell lymphoma (ALCL). Thus, better understanding of the molecular pathogenesis of these intractable diseases is warranted to develop effective therapies. In that effort, analysis of samples collected from patients with PTCL has been the gold standard for analysis of gene and protein expression, as well gene mutational profiles. However, it remains challenging to discover fundamental mechanisms that could be targeted based on analysis of samples with such heterogeneous backgrounds. Also, both the initiation and dynamic course of these diseases are difficult to pinpoint due to limitations on sample collection by their rarity. Nonetheless, recent analysis of patient samples has identified some mutational profiles and expression signatures for various types of PTCL that can be modeled in mice, which is an essential step in developing novel treatments.
In this chapter we describe several mouse lines established for angioimmunoblastic T‐cell lymphoma (AITL), ALCL, adult T‐cell leukemia/lymphoma (ATLL), cutaneous T‐cell lymphoma (CTCL) and enteropathy‐associated T‐cell lymphoma (EATL) (Summarized in Table 4.1). Most of the mouse lines are established by transgenic or knock‐in strategies commonly used to express oncogenes identified in patient samples. One advantage of transgenic models is that the transgene can be engineered to be expressed tissue‐specifically or responsive to a particular drug. Knock‐in models are superior to transgenic models in that oncogenic genes are expressed at physiological levels. Clustered regularly interspaced short palindromic repeats (CRISPR)‐Cas9, a powerful genome‐editing tool has begun to be incorporated in this research area. Moreover, patient‐derived xenograft (PDX models have been established by inoculating patient samples into immunodeficient mice. Ultimately, a