Professor Kaoru UCHIMARU
TEL: ＋81-3-5449-5298
E-mail: uchimaru{at}edu.k.u-tokyo.ac.jp
Associate Professor Kazumi NAKANO
TEL: +81-3-5449-5295
E-mail: nakanokz{at}edu.k.u-tokyo.ac.jp
nakanokz{at}ims.u-tokyo.ac.jp
【Key Words】HTLV-1, ATL, HTLV-1 Tax/Rex/HBZ, Host-pathogen interaction, ADC
In our laboratory Prof. Uchimaru majors in clinical hematology collaborating with Associate Professor Nakano who specialize virology. ATL (Adult T-cell Leukemia) is caused by human retrovirus HTLV-1 (Human T-cell Leukemia Virus type 1) which is transmitted to T cells of infants from HTLV-1 infected mothers mainly through breast milk feeding after long latency of about 60 years. ATL is intractable disease and is one of the hematological malignancies with poorest prognosis.HTLV-1 is transmitted through breast milk feeding from HTLV-1 infected mothers and sexual intercourse. The number of HTLV-1 infected people is estimated to be 10 to 20 million worldwide. Japan is one of the most endemic areas where the number of HTLV-1 infected people is estimated to be over one million. Most of the HTLV-1 infected people is asymptomatic through their lifetime and called asymptomatic carriers but about 5% of them finally develop intractable hematological malignancies called ATL and a few develop two inflammatory disease such as HTLV-1 associated myelopathy (HAM) and HTLV-1 uveitis (HU) after long latency about 6o years. Prognosis of ATL treated by chemotherapies is very poor. Recently hematopoietic stem cell transplantation is improving its prognosis along with newly developed molecular targeting drugs. One of the future directions is preemptive therapy to high- risk carriers thorough estimating the risk of ATL development in the HTLV-1 carriers. Prof. Uchimaru treats inpatient ATL patients and follow up many HTLV-1 asymptomatic carriers in outpatient clinic in Research Hospital, institute of Medical Sciences, the University of Tokyo and analyze clinical data. Along with these clinical studies, political research in Ministry of Health, Labor and Welfare to prevent HTLV-1 mother to child transmission and establish the system to deal HTLV-1 asymptomatic carriers is a major activity.
Associate professor Nakano is interested in the characteristics of HTLV-1 as an oncovirus. HTLV-1 is a single-stranded positive-sense RNA virus belonging to the genus Deltatretrovirus in the family Retroviridae. After infection, the viral genomic RNA undergoes reverse transcription and conversion to double-stranded DNA and is permanently incorporated into the human genomic DNA of host T cells as a provirus of approximately 9 kb with LTRs at both ends. The provirus contains all the genetic information necessary for viral replication. After infection, the virus replicates for 10 to 14 days using the transcription and translation mechanisms of the host cell, after which it quickly enters a latent infection state (Fig. 1). Thereafter, the infected cells become immortalized and are thought to survive in the carrier for several decades. In the early stages of infection, the provirus first transcribes Tax/Rex mRNA,which encodes Tax and Rex together, the major functional proteins of the virus, from the 5′-LTR. Also, HBZ mRNA, which encodes HBZ (HTLV-1 basic region leucine-zipper) is transcribed from the 3′-LTR. Tax specifically activates the 5′-LTR and promotes transcription of unspliced viral mRNA encoding Gag/Pro/Pol and partially-spliced viral mRNA encoding Env, the structural proteins of viral particles. Rex specifically binds to the RxRE motif in the 3'-UTR of these unspliced and partially-spliced viral mRNAs and rapidly transports them out of the nucleus and promotes virus particle formation by intervening in host cell transcription, translation, and mRNA quality control mechanisms to escort/protect viral mRNAs (Nakano et al., Microbes Infect. 15, 491–505. 2013; Viruses 14, 344. 2022; Viruses 14, 407. 2022). HBZ acts antagonistically with Tax to negatively regulate viral gene transcription, while increasing the efficiency of HTLV-1 infection and promoting the proliferation of infected T cells.
Dr. Nakano is also searching for target molecules in ATL cells. She has reported that proto-oncogenes, c-Myb (Nakano et al., Clin Cancer Res. 22: 5915-5928. 2016), Wnt5a (Nakano et al., Sci. Rep. 11: 4114. 2021), and FoxM1 (unpublished data) are overexpressed in ATL cells compared to normal T cells. Also, a mutant Caspase8, which normally induces apoptosis but contributes to ATL cell survival through its anti-apoptotic function, is overexpressed in ATL cells (Nakano et al., Mol. Cancer Res. 17: 2522-2536. 2019). At the moment, Dr. Nakano is developing an antibody-drug conjugate (ADC) that delivers drugs against those target molecules specifically to ATL cells in collaboration with the Graduate School of Engineering/the University of Tokyo, the University of the Ryukyus, St. Marianna University of Medicine, and the National Institute of Infectious Diseases (Fig. 3).
