HTLV-1: genetic and epigenetic factors associated with the development of adult t-cell leukemia/lymphoma




HTLV-1; Oncoproteins; Epigenetics.


Objective: Identify possible genetic and epigenetic factors associated with the development of adult T-cell leukemia/lymphoma. Methodology: This is a work based on the integrative review of the literature. The search for articles was performed using the descriptors indexed in the DeCS (Descriptors in Health Sciences) and MeSH (Medical Subject Headings), articles published in the last 5 years were included. Results and Discussion: The carcinogenesis process that culminates in the progression of ATLL has several phases over a long period of time. The beginning of the neoplastic process is related to the expression of viral oncoprotein Tax, which induces replication and initiation of the clonal expansion process. HBZ oncoprotein and HBZ RNA are continuously transcribed into neoplastic cells and influence the process of cell proliferation and viral persistence. In addition to genetic factors that are generally mediated by Tax and HBZ proteins, epigenetic changes are also required, such as histone acetylation and DNA methylation. Conclusion: it is then concluded that genetic factors such as Tax, HBZ, FYN, PLCG1, CD247, DLG1, VAV1, ERC1, PRKCQ, CARD11, RELA, IKBKB, TET1, TET2, MLL2, MLL3 DNMT1 e IRF4. And epigenetic pathways that act on DNA methylation and histone acetylation are involved in the HTLV-1-mediated carcinogenesis process.


Akbarin, M. M., Shirdel, A., Bari, A., Mohaddes, S. T., Rafatpanah, H., Karimani, E. G., Etminani, K., Golabpour, A., & Torshizi, R. (2017). Evaluation of the role of TAX, HBZ, and HTLV-1 proviral load on the survival of ATLL patients. Blood research, 52(2), 106–111.

Alessio, L., Minichini, C., Starace, M., Occhiello, L., Caroprese, M., Di Caprio, G., Sagnelli, C., Gualdieri, L., Pisaturo, M., Onorato, L., Scotto, G., Macera, M., De Pascalis, S., Sagnelli, E., & Coppola, N. (2018). Low prevalence of HTLV1/2 infection in a population of immigrants living in southern Italy. PLoS neglected tropical diseases, 12(6), e0006601.

Alvarez, C., Gotuzzo, E., Vandamme, A. M., & Verdonck, K. (2016). Family Aggregation of Human T-Lymphotropic Virus 1-Associated Diseases: A Systematic Review. Frontiers in microbiology, 7, 1674.

Bangham C. (2018). Human T Cell Leukemia Virus Type 1: Persistence and Pathogenesis. Annual review of immunology, 36, 43–71.

Bangham, C., & Matsuoka, M. (2017). Human T-cell leukaemia virus type 1: parasitism and pathogenesis. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 372(1732), 20160272.

Cheng, W., Zheng, T., Wang, Y., Cai, K., Wu, W., Zhao, T., & Xu, R. (2019). Activation of Notch1 signaling by HTLV-1 Tax promotes proliferation of adult T-cell leukemia cells. Biochemical and biophysical research communications, 512(3), 598–603.

Cook, L. B., Fuji, S., Hermine, O., Bazarbachi, A., Ramos, J. C., Ratner, L., Horwitz, S., Fields, P., Tanase, A., Bumbea, H., Cwynarski, K., Taylor, G., Waldmann, T. A., Bittencourt, A., Marcais, A., Suarez, F., Sibon, D., Phillips, A., Lunning, M., Farid, R., … Watanabe, T. (2019). Revised Adult T-Cell Leukemia-Lymphoma International Consensus Meeting Report. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 37(8), 677–687.

Futsch, N., Mahieux, R., & Dutartre, H. (2017). HTLV-1, the Other Pathogenic Yet Neglected Human Retrovirus: From Transmission to Therapeutic Treatment. Viruses, 10(1), 1.

Gazon, H., Belrose, G., Terol, M., Meniane, J. C., Mesnard, J. M., Césaire, R., & Peloponese, J. M., Jr (2016). Impaired expression of DICER and some microRNAs in HBZ expressing cells from acute adult T-cell leukemia patients. Oncotarget, 7(21), 30258–30275.

Giam, C. Z., & Semmes, O. J. (2016). HTLV-1 Infection and Adult T-Cell Leukemia/Lymphoma-A Tale of Two Proteins: Tax and HBZ. Viruses, 8(6), 161.

Harrod R. (2019). Silencers of HTLV-1 and HTLV-2: the pX-encoded latency-maintenance factors. Retrovirology, 16(1), 25.

Hartl, D. L., & Clark, A. G. (2010). Princípios de Genética de Populações-4. Artmed Editora.

Ichikawa, T., Nakahata, S., Fujii, M., Iha, H., Shimoda, K., & Morishita, K. (2019). The regulation of NDRG2 expression during ATLL development after HTLV-1 infection. Biochimica et biophysica acta. Molecular basis of disease, 1865(10), 2633–2646.

Kannagi, M., Hasegawa, A., Nagano, Y., Kimpara, S., & Suehiro, Y. (2019). Impact of host immunity on HTLV-1 pathogenesis: potential of Tax-targeted immunotherapy against ATL. Retrovirology, 16(1), 23.

Kanzaki L. (2018). HTLV-1: A real pathogen or a runaway guest of a diseased cell?. Journal of biosciences, 43(4), 785–795.

Kataoka, K., Nagata, Y., Kitanaka, A., Shiraishi, Y., Shimamura, T., Yasunaga, J., Totoki, Y., Chiba, K., Sato-Otsubo, A., Nagae, G., Ishii, R., Muto, S., Kotani, S., Watatani, Y., Takeda, J., Sanada, M., Tanaka, H., Suzuki, H., Sato, Y., Shiozawa, Y., … Ogawa, S. (2015). Integrated molecular analysis of adult T cell leukemia/lymphoma. Nature genetics, 47(11), 1304–1315.

Kataoka, K., Iwanaga, M., Yasunaga, J. I., Nagata, Y., Kitanaka, A., Kameda, T., Yoshimitsu, M., Shiraishi, Y., Sato-Otsubo, A., Sanada, M., Chiba, K., Tanaka, H., Ochi, Y., Aoki, K., Suzuki, H., Shiozawa, Y., Yoshizato, T., Sato, Y., Yoshida, K., Nosaka, K., … Ogawa, S. (2018). Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma. Blood, 131(2), 215–225.

Lyngdoh, D. L., Shukla, H., Sonkar, A., Anupam, R., & Tripathi, T. (2019). Portrait of the Intrinsically Disordered Side of the HTLV-1 Proteome. ACS omega, 4(6), 10003–10018.

Mahgoub, M., Yasunaga, J. I., Iwami, S., Nakaoka, S., Koizumi, Y., Shimura, K., & Matsuoka, M. (2018). Sporadic on/off switching of HTLV-1 Tax expression is crucial to maintain the whole population of virus-induced leukemic cells. Proceedings of the National Academy of Sciences of the United States of America, 115(6), E1269–E1278.

Malpica, L., Pimentel, A., Reis, I. M., Gotuzzo, E., Lekakis, L., Komanduri, K., Harrington, T., Barber, G. N., & Ramos, J. C. (2018). Epidemiology, clinical features, and outcome of HTLV-1-related ATLL in an area of prevalence in the United States. Blood advances, 2(6), 607–620.

Martinez, M. P., Al-Saleem, J., & Green, P. L. (2019). Comparative virology of HTLV-1 and HTLV-2. Retrovirology, 16(1), 21.

Matsuoka, M., & Mesnard, J. M. (2020). HTLV-1 bZIP factor: the key viral gene for pathogenesis. Retrovirology, 17(1), 2.

Mehta-Shah, N., Ratner, L., & Horwitz, S. M. (2017). Adult T-Cell Leukemia/Lymphoma. Journal of oncology practice, 13(8), 487–492.

Mendes, F. C., M., de Ribamar Oliveira Lima, J., de Oliveira de Melo, B., de Maria Fernandes da Silva Pinto, C., Maia, H. S., Ferro, T., Monteiro, S. G., Stancioli, E., & Bomfim, M. (2020). Molecular detection of human T cell lymphotropic virus type 1 in pregnant women from Maranhão state, Brazil. Brazilian journal of microbiology : [publication of the Brazilian Society for Microbiology], 51(2), 637–645.

Mohanty, S., & Harhaj, E. W. (2020). Mechanisms of Oncogenesis by HTLV-1 Tax. Pathogens (Basel, Switzerland), 9(7), 543.

Morais, M., Gato, C. M., Maciel, L. A., Lalwani, P., Costa, C. A., & Lalwani, J. (2017). Prevalence of Human T-lymphotropic virus type 1 and 2 among blood donors in Manaus, Amazonas State, Brazil. Revista do Instituto de Medicina Tropical de Sao Paulo, 59, e80.

Naito, T., Ushirogawa, H., Fukushima, T., Tanaka, Y., & Saito, M. (2019). EOS, an Ikaros family zinc finger transcription factor, interacts with the HTLV-1 oncoprotein Tax and is downregulated in peripheral blood mononuclear cells of HTLV-1-infected individuals, irrespective of clinical statuses. Virology journal, 16(1), 160.

Oliveira, P. D., Farre, L., & Bittencourt, A. L. (2016). Adult T-cell leukemia/lymphoma. Revista da Associacao Medica Brasileira (1992), 62(7), 691–700.

Phillips, A. A., & Harewood, J. (2018). Adult T Cell Leukemia-Lymphoma (ATL): State of the Art. Current hematologic malignancy reports, 13(4), 300–307.

Ratner L. (2020). Molecular biology of human T cell leukemia virus. Seminars in diagnostic pathology, 37(2), 104–109.

Rodríguez-Zúñiga, M. J., Cortez-Franco, F., & Qujiano-Gomero, E. (2017). Adult T-cell leukemia/lymphoma in a Peruvian hospital in human T-lymphotropic virus type 1 (HTLV-1) positive patients. International journal of dermatology, 56(5), 503–509.

Rowan, A. G., Dillon, R., Witkover, A., Melamed, A., Demontis, M. A., Gillet, N. A., Mun, L. J., Bangham, C., Cook, L. B., Fields, P. A., & Taylor, G. P. (2020). Evolution of retrovirus-infected premalignant T-cell clones prior to adult T-cell leukemia/lymphoma diagnosis. Blood, 135(23), 2023–2032.

Rushing, A. W., Rushing, B., Hoang, K., Sanders, S. V., Péloponèse, J. M., Jr, Polakowski, N., & Lemasson, I. (2019). HTLV-1 basic leucine zipper factor protects cells from oxidative stress by upregulating expression of Heme Oxygenase I. PLoS pathogens, 15(6), e1007922.

Saito M. (2019). Association Between HTLV-1 Genotypes and Risk of HAM/TSP. Frontiers in microbiology, 10, 1101.

Shudofsky, A., & Giam, C. Z. (2019). Cells of adult T-cell leukemia evade HTLV-1 Tax/NF-κB hyperactivation-induced senescence. Blood advances, 3(4), 564–569.

Sousa, L. M. M. S., Marques-Vieira, C. M. A., Severino, S. S., & Antunes, A. V. (2017). Metodologia de revisão integrativa da literatura em enfermagem.

Sugata, K., Yasunaga, J., Kinosada, H., Mitobe, Y., Furuta, R., Mahgoub, M., Onishi, C., Nakashima, K., Ohshima, K., & Matsuoka, M. (2016). HTLV-1 Viral Factor HBZ Induces CCR4 to Promote T-cell Migration and Proliferation. Cancer research, 76(17), 5068–5079.

Takiuchi, Y., Kobayashi, M., Tada, K., Iwai, F., Sakurada, M., Hirabayashi, S., Nagata, K., Shirakawa, K., Shindo, K., Yasunaga, J. I., Murakawa, Y., Rajapakse, V., Pommier, Y., Matsuoka, M., & Takaori-Kondo, A. (2017). HTLV-1 bZIP factor suppresses TDP1 expression through inhibition of NRF-1 in adult T-cell leukemia. Scientific reports, 7(1), 12849.

Tanaka, A., & Matsuoka, M. (2018). HTLV-1 Alters T Cells for Viral Persistence and Transmission. Frontiers in microbiology, 9, 461.

Tarokhian, H., Rahimi, H., Mosavat, A., Shirdel, A., Rafatpanah, H., Akbarin, M. M., Bari, A., Ramezani, S., & Rezaee, S. A. (2018). HTLV-1-host interactions on the development of adult T cell leukemia/lymphoma: virus and host gene expressions. BMC cancer, 18(1), 1287.

Uchida, Y., Yoshimitsu, M., Hachiman, M., Kusano, S., Arima, N., Shima, K., Hayashida, M., Kamada, Y., Nakamura, D., Arai, A., Tanaka, Y., Hara, H., & Ishitsuka, K. (2021). RLTPR Q575E: A novel recurrent gain-of-function mutation in patients with adult T-cell leukemia/lymphoma. European journal of haematology, 106(2), 221–229.

Watanabe T. (2017). Adult T-cell leukemia: molecular basis for clonal expansion and transformation of HTLV-1-infected T cells. Blood, 129(9), 1071–1081.

Yamagishi, M., Fujikawa, D., Watanabe, T., & Uchimaru, K. (2018). HTLV-1-Mediated Epigenetic Pathway to Adult T-Cell Leukemia-Lymphoma. Frontiers in microbiology, 9, 1686.

Yamagishi, M., Hori, M., Fujikawa, D., Ohsugi, T., Honma, D., Adachi, N., Katano, H., Hishima, T., Kobayashi, S., Nakano, K., Nakashima, M., Iwanaga, M., Utsunomiya, A., Tanaka, Y., Okada, S., Tsukasaki, K., Tobinai, K., Araki, K., Watanabe, T., & Uchimaru, K. (2019). Targeting Excessive EZH1 and EZH2 Activities for Abnormal Histone Methylation and Transcription Network in Malignant Lymphomas. Cell reports, 29(8), 2321–2337.e7.

Yasunaga J. I. (2020). Strategies of Human T-Cell Leukemia Virus Type 1 for Persistent Infection: Implications for Leukemogenesis of Adult T-Cell Leukemia-Lymphoma. Frontiers in microbiology, 11, 979.

Yeh, C. H., Bellon, M., Pancewicz-Wojtkiewicz, J., & Nicot, C. (2016). Oncogenic mutations in the FBXW7 gene of adult T-cell leukemia patients. Proceedings of the National Academy of Sciences of the United States of America, 113(24), 6731–6736.

Zhang, L. L., Wei, J. Y., Wang, L., Huang, S. L., & Chen, J. L. (2017). Human T-cell lymphotropic virus type 1 and its oncogenesis. Acta pharmacologica Sinica, 38(8), 1093–1103.

Zhang, L., Lu, Q., & Chang, C. (2020). Epigenetics in Health and Disease. Advances in experimental medicine and biology, 1253, 3–55.

Zhao T. (2016). The Role of HBZ in HTLV-1-Induced Oncogenesis. Viruses, 8(2), 34.



How to Cite

ANJOS, G. H. S. dos; TENÓRIO, K. E. R. . HTLV-1: genetic and epigenetic factors associated with the development of adult t-cell leukemia/lymphoma. Research, Society and Development, [S. l.], v. 11, n. 7, p. e26211729781, 2022. DOI: 10.33448/rsd-v11i7.29781. Disponível em: Acesso em: 6 jul. 2022.



Review Article