The Peripheral T-Cell Lymphomas. Группа авторов
of human ATL. HBZ transgenic mice constructed using the GrzmB promoter were also reported [38] and exhibited lymphoproliferative disease, osteoporosis, splenomegaly, and hypercalcemia, similar to lymphoma‐type of ATLL. HBZ/Tax double transgenic mice in which both genes were controlled by the Cd4 promoter showed phenotypes similar to those of HBZ single transgenic mice [39]. Despite this progress, to date a model fully replicating human ATLL disease has not yet been established likely due to the complexity of the human ATLL disease.
PDX Models of Adult T‐cell Leukemia/Lymphoma
Xenograft mouse models transplanted with ATLL patient‐derived cells have been examined [40]. In these models, immunodeficient SCID and NOD/SCID recipient mice displayed multiple features of human ATLL disease, namely, aberrant lymphocyte infiltration in liver, spleen, lung, peritoneum, and other organs. These models have helped define mechanisms underlying HTLV1 infection, clonal proliferation and the immune response against HTLV1 and have contributed to development of targeted therapies. For example, treatments using the antibody against C─C chemokine receptor type 4 and an inhibitor of histone deacetylase have been tested in these models.
Cutaneous T‐cell Lymphoma
CTCL contains a broad spectrum of diseases: Mycosis fungoides and Sézary syndrome account for more than 60% of CTCL. The tumor cells of Mycosis fungoides and Sézary syndrome represent CD4+ helper T cells. Several CTCL models have been established to define mechanisms underlying CTCL and identify therapeutic targets. Patients with CTCL show high IL‐15 protein levels in the skin. Hypermethylation within the IL‐15 promoter suppresses binding of the ZEB1 transcriptional repressor to the locus, leading to increase of IL‐15 transcription in CD4+ T cells [41]. Fehniger et al. reported a transgenic mouse model using the MHC class I promoter to drive IL‐15 expression [42]. IL‐15 transgenic mice developed fatal leukemia with involvement of multiple organs including skin around 12–30 weeks and have served as a preclinical CTCL model and were useful in the discovery that interruption of IL‐15 signaling via an HDAC inhibitor is a promising treatment strategy for CTCL [41, 42].
JAK3‐activating mutations are recurrently observed in CTCL [43]. Human JAK3 shows four mutation hotspots: M511I, R657Q, A572V, and 573V. Cornejo et al. reported the retroviral transduction of active JAK3A572V mutant cDNA into 5‐fluorouracil‐treated murine bone marrow cells followed by transplantation into lethally irradiated mice [44]. The recipient mice developed CD8+ lymphoproliferative diseases with skin involvement, mimicking a leukemic form of CTCL [44]. Rivera‐Munoz et al. generated a JAK3A572V knock‐in mouse model expressing the JAK3A572V mutant from the endogenous Jak3 locus also developed a leukemic form of CTCL [45]. Phosphorylation of downstream targets of JAK3 was dose dependent: phospho‐Stat3 and Stat5 were observed even in thymocytes from heterozygous JAK3A572V mutant mice, while phospho‐Akt and Erk1/2 were seen only in those of homozygous. Treatment with tofacitinib, a pan‐JAK inhibitor reduced growth of JAK3A572V‐positive CD4+ and CD8+ malignant cells. This result suggests that inhibition of constitutively activated JAK3 may improve treatment outcomes of CTCLs.
Enteropathy‐associated T‐cell Lymphoma
EATL is a rare but fatal PTCL arising from the intestinal tract. Genomic alterations in SETD2 gene resulting in SETD2 loss of function, and/or loss of the corresponding 3p.21 locus are found in 31–86% of EATL [46, 47]. SETD2 encodes a non‐redundant H3K36‐specific tri‐methyltransferase that serves as a tumor suppressor. In SETD2‐mutated EATL samples, H3K36me3 expression in tumor specimens was either defective or very weak. To further investigate SETD2 function in T‐cell development, the Setd2 cKO mice were generated with Lck‐Cre transgenic mice [47]. After comparing the proportion of intraepithelial T cells in Setd2 wild‐type versus deficient mice, they observed a significant increase in the population of γδ‐positive T cells in Setd2‐deficient mice. Although these mice do not perfectly recapitulate human EATL, this model may provide a very useful tool for future modeling of this fatal disease and is being evaluated in preclinical studies.
Conclusion
Over the years, murine models have played crucial roles as versatile tools for detailed investigation of T‐cell lymphomas. We now have a deeper understanding of the underlying mechanisms, disease pathogenesis and potential therapeutic interventions. Nevertheless, it is essential to understand the limitations of these model systems. Lack of precise simulation of the human disease and the microenvironment in mice are few among many shortcomings that hinder the success of novel drugs in clinical trials. The advent of targeted genetic manipulation using novel technologies may eventually resolve and refine the remaining differences making mouse the ultimate model organism of choice to study human ailments.
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