Shunro Sonoda

Improved outcome of adult T cell leukemia/lymphoma with allogeneic hematopoietic stem cell transplantation.

Adult T cell leukemia/lymphoma (ATL) is a poor prognosis T cell malignancy. In order to improve the outcome, we employed allogeneic stem cell transplantation (allo-SCT) for ATL in 10 patients, nine of whom were from HLA-identical siblings and one from an unrelated donor. Conditioning regimens varied among the patients except that all received total body irradiation. The patients tolerated the regimens well with mild, if any toxicity, and engraftment occurred in all cases. Median leukemia-free survival after allo-SCT was 17.5+ months (range 3.7–34.4+). Six of the 10 patients developed acute GVHD (one case each with grade I, III or IV, and three cases with grade II) and three patients developed extensive chronic GVHD. Four patients died after allo-SCT during the study period from either acute GVHD (grade IV), pneumonitis, gastrointestinal bleeding or renal insufficiency. Two of the 10 cases with no symptoms of GVHD relapsed with clinical ATL. These results strongly suggest that allo-SCT may improve the survival in ATL if a controlled degree of GVHD develops. Bone Marrow Transplantation (2001) 27, 15–20.

The presence of ancient human T-cell lymphotropic virus type I provirus DNA in an Andean mummy

The worldwide geographic and ethnic clustering of patients with diseases related to human T-cell lymphotropic virus type I (HTLV-I) may be explained by the natural history of HTLV-I infection. The genetic characteristics of indigenous people in the Andes are similar to those of the Japanese, and HTLV-I is generally detected in both groups. To clarify the common origin of HTLV-I in Asia and the Andes, we analyzed HTLV-I provirus DNA from Andean mummies about 1,500 years old. Two of 104 mummy bone marrow specimens yielded a band of human β-globin gene DNA 110 base pairs in length, and one of these two produced bands of HTLV-I-pX (open reading frame encoding p40x, p27x) and HTLV-I-LTR (long terminal repeat) gene DNA 159 base pairs and 157 base pairs in length, respectively. The nucleotide sequences of ancient HTLV-I-pX and HTLV-I-LTR clones isolated from mummy bone marrow were similar to those in contemporary Andeans and Japanese, although there was microheterogeneity in the sequences of some mummy DNA clones. This result provides evidence that HTLV-I was carried with ancient Mongoloids to the Andes before the Colonial era. Analysis of ancient HTLV-I sequences could be a useful tool for studying the history of human retroviral infection as well as human prehistoric migration.

Characteristic distribution of HTLV type I and HTLV type II carriers among native ethnic groups in South America.

To confirm the geographic and ethnic segregation of HTLV-I and HTLV-II carriers in native populations in South America, we have conducted a seroepidemiological study of native populations in South America, including HTLV-I carriers distributed among seven ethnic groups in the Andes highlands of Colombia, Peru, Bolivia, Argentina, and Chile, and two ethnic groups on Chiloe Island and Easter Island; and HTLV-II carriers distributed among seven ethnic groups of the lowlands along the Atlantic coast of Colombia, Orinoco, Amazon, and Patagonia, and one ethnic group on Chiloe Island. The incidence rate of HTLV-I and HTLV-II carriers varied among the ethnic groups, ranging from 0.8 to 6.8% for HTLV-I seropositivity and from 1.4 to 57.9% for HTLV-II seropositivity. A new HTLV-I focus was found among the Peruvian Aymara (1.6%), the Bolivian Aymara (5.3%) and Quechua (4.5%), the Argentine Puna (2.3%), and the Chilean Atacama (4.1%), while on HTLV-II focus was found among the Brazilian Kayapo (57.9%), the Paraguayan Chaco (16.4%), and the Chilean Alacalf (34.8%) and Yahgan (9.1%). The distribution of HTLV-I/II foci showed a geographic clustering of HTLV-I foci in the Andes highlands and of HTLV-II foci in the lowlands of South America. It was thus suggested that South American natives might be divided into two major ethnic groups by HTLV-I and HTLV-II carrier state.

Ancient HTLV type 1 provirus DNA of Andean mummy.

The worldwide geographic and ethnic clustering of patients with diseases related to human T cell lymphotropic virus type 1 (HTLV-1) may be explained by the natural history of HTLV-1 infection. The genetic characteristics of indigenous people in the Andes are similar to those of the Japanese, and HTLV-1 is generally detected in both groups. To clarify the common origin of HTLV-1 in Asia and the Andes, we analyzed HTLV-1 provirus DNA from Andean mummies about 1500 years old. Two of 104 mummy bone marrow specimens yielded a band of human beta-globin gene DNA 110 base pairs in length, and one of these two produced bands of HTLV-1-pX (open reading frame encoding p(40x), p(27x)) and HTLV-1-LTR (long terminal repeat) gene DNA 159 base pairs and 157 base pairs in length, respectively. The nucleotide sequences of ancient HTLV-1-pX and HTLV-1-LTR clones isolated from mummy bone marrow were similar to those in contemporary Andeans and Japanese, although there was microheterogeneity in the sequences of some mummy DNA clones. This result provides evidence that HTLV-1 was carried with ancient Mongoloids to the Andes before the Colonial era. Analysis of ancient HTLV-1 sequences could be a useful tool for studying the history of human retroviral infection as well as human prehistoric migration.

Integration of human T‐cell leukemia virus type 1 in genes of leukemia cells of patients with adult T‐cell leukemia

Adult T‐cell leukemia (ATL) occurs after a long latent period of persistent infection by human T‐cell leukemia virus type 1 (HTLV‐1). However, the mechanism of oncogenesis by HTLV‐1 remains to be clarified. It was reported that the incidence curve of ATL versus age was consistent with a multistage carcinogenesis model. Although HTLV‐1 is an oncogenic retrovirus, a mechanism of carcinogenesis in ATL by insertional mutagenesis as one step during multistage carcinogenesis has not been considered thus far, because the exact integration sites on the chromosome have not been analyzed. Here we determined the precise HTLV‐1 integration sites on the human chromosome, by taking advantage of the recently available human genome database. We isolated 25 integration sites of HTLV‐1 from 23 cases of ATL. Interestingly, 13 (52%) of the integration sites were within genes, a rate significantly higher than that expected in the case of random integration (P=0.043, ?2 test). These results suggest that preferential integration into genes at the first infection is a characteristic of HTLV‐1. However considering that some of the genes are related to the regulation of cell growth, the integration of HTLV‐1 into or near growth‐related genes might contribute to the clonal selection of HTLV‐1‐infected cells during multistage carcinogenesis of ATL.

Successful bone marrow transplantation from an unrelated donor in a patient with adult T cell leukemia

We report a 51-year-old male with adult T cell leukemia (ATL) who received a BMT from an HLA-identical unrelated donor. The ATL proved refractory to chemotherapy, and he underwent BMT conditioned with CY/TBI. Complications of encephalitis of unknown origin were successfully treated with steroid therapy and the patient has been in CR for 16 months after BMT. Human T cell leukemia virus type 1 proviral DNA loads were reduced to undetectable levels in PBMC sampled 12 months after BMT. This encouraging result suggests that BMT from an unrelated donor should be considered for ATL even if the disease is refractory to chemotherapy.

β-Globin Gene Haplotype Characteristics of Colombian Amerinds in South America

Haplotypes and subhaplotypes in the β-globin gene cluster were identified in 146 and 156 chromosomes, respectively, of three tribes of Colombian Amerinds. Subhaplotype [+––––] was a major one in Colombian Amerinds as in most human ethnic groups except Africans. A major subhaplotype [––––+] in Africans was observed in only one chromosome. The framework 2 frequencies were very low (0.018–0.067). Haplotype [+––––++], which is a major one in Europeans, but not in Asians, and [+–––––+], which is a major one in Asians, but not in Europeans, were two major haplotypes. Subhaplotype data showed the closest genetic affinities between Colombian Amerinds and Polynesians, Micronesians, and Asians, but the haplotype data did not necessarily support this.