The Peripheral T-Cell Lymphomas. Группа авторов
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140 140 Lai, Q., Wang, H., Li, A. et al. (2018). Decitibine improve the efficiency of anti‐PD‐1 therapy via activating the response to IFN/PD‐L1 signal of lung cancer cells. Oncogene 37 (17): 2302–2312.
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 combination of all these approaches will be necessary to understand mechanisms driving initiation and progression of PTCL.
Table 4.1 Mouse models of peripheral T‐cell lymphomas (PTCL)
Types of PTCL | Models | Methods | Phenotypes of mice | Others (downstream signaling, etc.) | Reference |
---|---|---|---|---|---|
AITL | Roquinsan | Heterozygous for Roquinsan : a missense (M199R) sanroque mutation in the Roquin gene | Increase of TFH cells AITL‐like disease around 4 to 15 months | No ROQUIN gene alterations in human AITL | Ellyard4 |
Tet2 gene trap | A gene‐trap vector inserted into the Tet2 second intron | Development of T‐cell lymphomas with TFH‐like phenotype around 67 weeks | Hypermethylation of silencer region of Bcl6 gene | Muto10 | |
G17V RHOA | G17V RHOA cKI mice crossed with CD4Cre‐ERT2 | Increase of TFH cells | Cortes14 | ||
G17V RHOA transgenic mice under the Cd4 promoter | Increase of TFH cells Autoimmunity | Ng15 | |||
G17V RHOA transgenic mice under the CD2 promoter | No phenotype | Nguyen16 | |||
G17V RHOA‐Tet2 null | Retroviral transduction of G17V RHOA mutant cDNA into Tet2‐null T cells | Increase of TFH cells CD4+ proliferation | Inactivation of FoxO1 | Zang13 | |
G17V RHOA cKI mice crossed with CD4CreERT2 and Tet2cKO with SRBC immunization | AITL‐like disease around 25 weeks | ICOSL‐ICOS signaling Activation of PI3K‐mTOR signaling | Cortes14 | ||
G17V RHOA transgenic mice crossed with Tet2cKO x Vav‐Cre, and OT‐II mice with NP‐40‐Ovalbumin immunization | AITL‐like disease around 38 weeks | Activation of PI3K‐mTOR signaling | Ng15 | ||
G17V RHOA transgenic mice crossed with Tet2cKO x Mx1‐Cre mice | AITL‐like disease around 48 weeks | Activation of T‐cell receptor signaling | Nguyen16 | ||
PDX | Inoculation of cells from lymph nodes of AITL patients into NOD/Shi‐scid, IL2Rgammanull (NOG) mice | AITL‐like disease | Detection of human immunoglobulin G/A/M in the sera | Sato18 | |
ALCL | NPM1‐ALK | Retroviral transduction of NPM1‐ALK cDNA into 5‐ fluorouracil‐treated murine BM |
B‐lineage large cell lymphomas
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