Laboratory of Tumor Cell Biology/
Laboratory of Viral Oncogenesis Recruiting students for the academic year 2018

Professor Kaoru UCHIMARU
E-mail: uchimaru{at}

Lab HP(Under Construction)

Associate Professor Hitoshi SATOH
E-mail: hitsatoh{at}

Associate Professor Kazumi NAKANO
(Laboratory of Viral Oncogenesis)
E-mail: nakanokz{at}


Uchimaru Group

【Key Words】HTLV-1, ATL, epigenome, EZH2, HTLV-1 Tax, HTLV-1 Rex

In Prof. Uchimaru’s group, researchers in the Laboratory of Tumor Biology are in corroboration with Dr. Nakano in Laboratory of Viral Oncogenesis to study ATL (adult T-cell leukemia/lymphoma), which is caused by infection of human retrovirus, HTLV-1 (Human T-cell Leukemia Virus type-1). Our goal is to clarify the genetic and molecular disorders accumulated in the HTLV-1 infected T cells, which cause the onset of ATL, for development of new therapeutic approach to ATL.
HTLV-1 is mainly transmitted to infants from infected mothers through breastfeeding, and leads to malignant transformation of infected T cells 60~70 years after the infection. The underlying molecular mechanisms of HTLV-1 pathogenesis and the genetic/epigenetic disorders responsible for the onset of ATL are poorly understood. Therefore, ATL is still one of the most aggressive T cell malignancies without effective cures. We speculate that genetic and molecular lesions at the time of HTLV-1 infection trigger further accumulation of molecular disorders in infected T cells, which cause immortalization and malignant transformation in these cells, followed by a monoclonal expansion of ATL leukemic cells. To uncover cellular events responsible for the ATL-onset, we focus on two aspects of this disease; (1) molecular disorders accumulated in ATL cells, and (2) deregulation of cellular pathways by HTLV-1 infection, and combine outcomes from those two approaches to understand the molecular mechanisms of ATL leukemogenesis triggered by HTLV-1 infection. Also, our research covers; (3) another human retrovirus HIV-1 to achieve the cure for AIDS and related diseases, as well as to further understand the molecular pathogenesis of human retroviruses, i.e., HIV-1 to AIDS and HTLV-1 to ATL (Fig. 1).

(1) Molecular dysregulation in ATL cells
In order to clarify molecular dysregulation in gene expression at various levels, we have been investigating mRNA and microRNA expression profiles, as well as splicing patterns in blood samples from ATL patients using various microarray technologies. Based on the comprehensive/comparative analysis of these data, we found abnormal overexpression of the epigenetic factor (EZH2), transcription factors (c-Myb, FoxM1), and a non-canonical Wnt ligand (Wnt5a), together with a complete loss of tumor-suppressive miR-31 in ATL cells. We also found a drastic accumulation of aberrant splicing mRNA variants in ATL cells. Our experiments show that accumulation of these genetic disorders is responsible for leukemogenesis and the malignancy of ATL cells (Yamagishi et al., 2012; Nakano et al., 2016) (Fig. 2).
We also focus on the pathological molecular network involving epigenetic deregulation in ATL cells. Particularly, we recently found through a genome-wide epigenetic analysis in ATL and HTLV-1 infected cells using the ChIP-on-chip technology that overexpression/disorder of polycomb family proteins EZH1/2 were responsible for reprogramming of epigenome causing abnormal gene expression profiles, thus downstream cellular signaling pathways in ATL cells. Therefore, EZH1/2 are promising therapeutic molecular targets for malignant neoplasms including ATL and other cancers (Fujikawa et al., 2016; Kobayashi et al., 2014; Yamagishi et al., 2012). Development and clinical trials of new drugs targeting EZH2 as well as EZH1 are in progress (Fig. 2).

(2) How does HTLV-1 infection affect the cellular homeostasis?
After HTLV-1 entry, the viral genomic RNA is reverse-transcribed and immediately integrated into the host human genome (provirus). Then, transcription and translation from the HTLV-1 provirus occur through the host cell machinery. We are particularly interested in the function of the viral transcription regulator, Tax, and mRNA transporter, Rex, in the HTLV-1 life-cycle, since they play major roles to utilize the host gene expression mechanism for viral replication. Rex is known to nuclear-export unspliced and partially spliced viral mRNAs. Further, we have found that Rex inhibits the cellular nonsense-mediated mRNA decay (NMD) to protect viral mRNAs and enhances production of viral proteins (Nakano et al., 2013). Tax strongly stimulates the proviral promoter and transacrivates viral expression. Our study has
demonstrated that Tax also interacts with various cellular proteins, including EZH2. Thus, Tax is involved in the cellular epigenetic regulation (Fujikawa et al., 2016). Our study reveals that these viral proteins hijack and fine-tune the host cellular mechanism beneficial for viral replication (Nakano and Watanabe, 2016). We continue to investigate how Tax and Rex alter the cellular homeostasis, thus how trigger immortalization and leukemogenesis of HTLV-1 infected T cells (Fig. 3).

(3) Molecular pathogenesis of human retroviruses
We are also working on the molecular mechanism of AIDS-related problems, especially HIV-1 latency (Matsuda et al., 2015) and AIDS-associated malignant lymphomas (Yamagishi et al., 2015).

<Our recent publications>

  1. Fujikawa D, Nakagawa S, Hori M, Kurokawa N, Soejima A, Nakano K, Yamochi T, Nakashima M, Kobayashi S, Tanaka Y, Iwanaga M, Utsunomiya A, Uchimaru K, Yamagishi M, Watanabe T. Polycomb-dependent epigenetic landscape in adult T-cell leukemia. Blood. 2016. 127:1790-802.
  2. Nakano K, Uchimaru K, Utsunomiya A, Yamaguchi K, Watanabe T. Dysregulation of c-Myb pathway by aberrant expression of proto-oncogene MYB provides the basis for malignancy in adult T-cell Leukemia/lymphoma cells. Clin Cancer Res. 2016. 22; 5915–28.
  3. Nakano K Watanabe T. HTLV-1 Rex tunes the cellular environment favorable for viral replication. Viruses. 2016. 8: 58.
  4. Matsuda Y, Kobayashi-Ishihara M, Fujikawa D, Ishida T, Watanabe T, Yamagishi M. Epigenetic heterogeneity in HIV-1 latency establishment. Sci Rep. 2015. 5:7701.
  5. Yamagishi M, Katano H, Hishima T, Shimoyama T, Ota Y, Nakano K, Ishida T, Okada S, Watanabe T. Coordinated loss of microRNA group causes defenseless signaling in malignant lymphoma.Sci. Rep. 2015. 5:17868.
  6. Kobayashi S, Nakano K, Watanabe E, Ishigaki T, Ohno N, Yuji K, Oyaizu N, Asanuma S, Yamagishi M, Yamochi T, Watanabe N, Tojo A, Watanabe T, Uchimaru K. CADM1 expression and stepwise downregulation of CD7 are closely associated with clonal expansion of HTLV-I-infected cells in adult t-cell leukemia/lymphoma. Clin Cancer Res. 2014. 20:2851-61.
  7. Nakano K, Ando T, Yamagishi M, Yokoyama K, Ishida T, Ohsugi T, Tanaka Y, Brighty DW, Watanabe T. Viral interference with host mRNA surveillance, the nonsense-mediated mRNA decay (NMD) pathway, through a new function of HTLV-1 Rex: implications for retroviral replication. Microbes Infect. 2013. 15:491-505.
  8. Yamagishi M, Nakano K, Miyake A, Yamochi T, Kagami Y, Tsutsumi A, Matsuda Y, Sato-Otsubo A, Muto S, Utsunomiya A, Yamaguchi K, Uchimaru K, Ogawa S, Watanabe T. Polycomb-mediated loss of miR-31 activates NIK-dependent NF-kB pathway in adult T-cell leukemia and other cancers. Cancer Cell. 2012 21:121-135.

Satoh Group

Dr. Satoh is working on the molecular mechanisms of chromosomal translocations and functions of chimeric genes found in leukemias and lymphomas by combining cytogenetic techniques (FISH, CGH) and modern techniques in genome sciences such as next generation sequencing.


The University of Tokyo
Graduate School of Frontier Sciences, The University of Tokyo

Page Top