Table 1.
Summary of the contribution of mouse models to ATL biology.
| Model | Contribution to ATL biology | Reference |
|---|---|---|
| Xenografts | ||
| Xenograft mouse models injected with HTLV-I transformed, ATL-derived cell lines or ATL patients derived cells | Represented a platform for targeted drug development. Provided a potential tool to test therapeutic agents:– Targeting the constitutively active NF-κB pathway. – Specifically targeting leukemic cells. Allowed a better understanding of the immune response against HTLV-I. Was instrumental for studying early stages of primary HTLV-I infection and subsequent clonal proliferation. Allowed the assessment of early steps of HTLV-I infection, proviral load, and clonal proliferation. | Zimmerman et al., 2011;Ishitsuka et al., 2012;Masaki et al., 2013;Saitoh et al., 2016,Phillips et al., 2000;Zhang et al., 2003, 2005;Maeda et al., 2010, 2015,Ishihara et al., 1992;Feuer et al., 1995;Stewart et al., 1996;Uchiyama, 1996;Liu et al., 2002,Miyazato et al., 2006,Takajo et al., 2007 |
| Humanized | ||
| HTLV-I infected human CD34+ in Rag2-/- gamma c-/- mice models | Allowed the understanding of early infection stages. Confirmed the in vivo correlation of Tax and NF-κB activation upon expansion of CD4+CD25+ malignant cells. | Villaudy et al., 2011 |
| HTLV-I infected human CD133+ in NSG | Generated a human adaptive immune system in immunodeficient mice. Was the closest model to recapitulate the in vivo ATL development.Assessed the initiated immune system against the virus and clonal selection. | Tezuka et al., 2014 |
| Tax TransgenicsLTR-Tax-Tg | Established Tax as an oncoprotein and HTLV-I as transforming virus resulting in mesenchymal tumors and neurofibroma. | Hinrichs et al., 1987;Nerenberg et al., 1987 |
| Showed that Tax expression in oxidative fibers resulted in HTLV-I associated myopathies. | Nerenberg and Wiley, 1989 | |
| Showed that Tax induced autoimmune like Sjogren like syndrome. | Green et al., 1989 | |
| Showed that Tax induced skeletal abnormalities and fragile bones similar to ATL patients. | Ruddle et al., 1993 | |
| Showed that Tax is arthrogenic and induced ankylotic arthropathy. | Habu et al., 1999 | |
| Showed that Immune system activation contributes to ATL pathogenesis in infected carriers. | Swaims et al., 2010 | |
| Double transgenic -βgal-Tg modelLTR-Tax HTLV-I LTR | Unveiled tissues supporting tax-mediated transcriptional transactivation. Provided a model system to study the mechanism of gene regulation by Tax. | Bieberich et al., 1993 |
| huGMZBTaxGMZ-Tax-TgGranzyme promoter | First model to generate leukemia (LGL), tumor infiltration, and splenomegaly partly resembling ATL. | Grossman et al., 1995 |
| Showed that Tax functionally inactivates P53 contributing to late stage tumor progression. | Portis et al., 2001 | |
| Showed that innate immune system, specifically IFN-γ, is crucial for ATL development. | Mitra-Kaushik et al., 2004 | |
| Revealed malignant hypercalcemia and osteolytic bone lesions resembling human ATL. | Gao et al., 2005 | |
| Showed that Tax expression in vivo induced constitutive activation of HTLV-I. | Bernal-Mizrachi et al., 2006 | |
| Revealed that Tax activation of lymphocytes recruits, activates, and transforms NK/T-cells. | Rauch et al., 2009b | |
| CD3- Tax TgCD3-epsilon promoter/enhancer | Model failed to develop leukemia. Tax expression closely associated with apoptosis in vivo. | Hall et al., 1998 |
| tTA/Tax miceBi-transgenic doxycycline inducible model, EmuSR alpha promoter-enhancer | Revealed ATL-like cutaneous lesions and splenomegaly via HTLV-I activation. Showed that Tax or HTLV-I suppression resolves cutaneous symptoms. | Kwon et al., 2005 |
| lck-Tax-tg modelLck-proximal promoter | Showed diffuse large cell lymphoma after prolonged latency. Model exhibits acute ATL like symptoms and HTLV-I activation. | Hasegawa et al., 2006 |
| Provided a candidate ATL stem cells of CD38-/CD71-/CD117+ phenotype and decreased expression of Tax, Notch, BMI1 were isolated. | Yamazaki et al., 2009 | |
| lck-Tax-tg modelLck-Distal promoter | Showed leukemia of mature CD4+ cells resembling mature CD4+ ATL cells | Ohsugi et al., 2007b |
| HBZ transgenicHBZ-Tg modelCD4-specific promoter/enhancer/silencer | Showed systemic inflammation and later lymphoma in 30% of mice upon aging. | Satou et al., 2011 |
| Increased effector/memory CD4+ cells and functionally impaired CD4+ Foxp3+ Treg cells. | Yamamoto-Taguchi et al., 2013 | |
| Showed that HBZ promotes a pro-inflammatory phenotype via labile Foxp3 expression. | Sugata et al., 2012 | |
| Showed that HBZ suppresses Th1 cytokines and impairs cell-mediated immunity. | Kuribayashi et al., 2016 | |
| HBZ-Tg mice exhibit ATL stem cells of c-kit+/CD4-/CD8- phenotype. | ||
| Double Transgenic Tax/HBZHBZ/Tax modelCD4 promoter/enhancer | This model failed to generate ATL-like leukemia. Skin lesions, T-cell lymphoma, and splenomegaly with increased CD4+ memory and Foxp3+Treg cells. | Zhao et al., 2014 |