H-104 ATL, ADF and human virus research
Authors: Yodoi Junji 
Published: April 2019

Prehistory of ATL Discovery and ADF/TRX.

More than 40 years have passed since our initial description of peculiar cases of adult-onset leukemia with abnormal cells having multi-convoluted nuclei and T cellproperties, frequent in the southern regions of Japan in the early 1970s.

In the initiation of Adult T-Cell Leukemia (ATL) research, both of my mentors Drs. Kimishige Ishizaka and Kiyoshi Takatsuki have been involved.

Dr. Kiyoshi Takatsuki was a kind of hero of our medical school in B cell malignancy multiple myeloma and Heavy Chain Diseases. Dr. Kimishige Ishizaka, Discoverer of Immunoglobulin E (IgE) reaginic antibody, and Dr. Takatsuki had been working in the field of Immunoglobulin and myeloma proteins with great pioneers including late H Kunkel, and EF Osserman.

Before my first description of ATL Cases with Dr. Takatsuki and the active instruction of late Dr. Toru Masuda in the Institute for Virus Res (IVR) of Kyoto Univ. returning from the Late Dr. L Herzenberg in Stanford Univ., I had been involved in the study of peculior myeloma-related disease, POEMS Syndrome/Takatsuki Disease/Crow-Fukase Syndrome. The POEMS Syndrome are characterized by polyneuropathy, organomegaly, endocrinopathy, myeloma protein, and skin changes. Drs. Y. Nishitani and Late M. Fukase in Kyoto Univ. also contributed in this Takatsuki Disease/Syndrome research. Indeed, Dr. Takatsuki was a kind of hero of our medical school in B cell malignancy multiple myeloma and HeavyChain Diseases, before ATL and HTLV.

Retrospectively, the study of adult T cell leukemia (ATL) and the related virus HTLV-I was a forerunner for all of human retrovirology, in which AIDS and the related retrovirus HIV were identified a few years later in the 1980s. I remember the great contribution of late Dr. Yohei Ito, who had initiated the cooperative interaction between Kyoto and Dr. Gallo in NCI in 70's. Using the anti-TAC monoclonal antibody generated by the late Dr. Takashi Uchiyama, my close colleague, during his stay in Dr. T. A. Waldmann's laboratory in NIH Bethesda, a cDNA encoding IL-2Ra chain was cloned by our group in Kyoto and by Waldmann's group in Bethesda. Abnormal IL-2Ra chain expression and the IL-2 dependency of ATL cell lines greatly contributed to the study of leukemogenesis of ATL. A new soluble factor named ADF/ATL-derived factor was also detected in ATL cell lines. Dr. Michiyuki Maeda greatly contributed establishing many ATL cell lines with his green thumb. After years of study, ADF proved to be a first human counterpart of thiol-related oxido-reductase thioredoxin/TRX, which opened the field of redox regulation of cell signaling involved in a variety of diseases. Quite interestingly, TRX-family member protein, GIF/MIF involved in the IgE regulation was characterized by the group of Dr. K. Ishizaka who have moved from J. Hopkins Univ. Baltimore to La Jolla, LIAI. Close interaction among Drs. Kimishige Ishizaka, Kiyoshi Takastuki and T. A. Waldmanns before ATL and HTLV-I study was an essential base for our initiation of ATL research with late Takashi Uchiyama and many other close colleagues. I remember Dr. Gallo's helpful comment on the importance of the 3 Letter naming of ATL and ADF.

In the therapeutic directions of ATL, monoclonal antibody seems to be still struggle: (1) Anti-Tac IL-2Ra Chain Therapies have been geared by TA Waldmann Group with many coworkers. However, the therapeutic effectiveness may be limited; (2) Anti-CCR4 mAbs applied to ATL cases by Dr. R Ueda Group in Japan is therapeutically effective. However high frequency of severe side effect namely Stevens-Johnson Syndrome, Toxic Epidermal Necrolysis (SJS/TEN) have been reported.

I may recall great contribution of late Drs. Takashi Uchiyama, Mitsuru Tsudo, Kazumasa Usami in Kyoto Univ. and Thomas Tursz of IGR Paris in our early ATL and ADF research. This paper is also dedicated for late Dr. Kimishige Ishizaka, discoverer of IgE and my great mentor close to Dr. Kiyoshi Takatsuki.