No abstract

The genome of human T-cell leukemia virus (HTLV) was surveyed in fresh tumor cells of 163 patients with lymphoma and leukemia from the southwest part of Japan where adult T-cell leukemia (ATL) is endemic. Leukemic cells of all 88 cases of ATL tested so far were found to contain the provirus genome and also found to be monoclonal with respect to the integration site of provirus genome. In most cases of ATL, leukemic cells contained one or two copies of the complete HTLV provirus genome, and it was shown that the single species of HTLV with a fully determined sequence is typical in ATL. Some cases of T-cell malignancies, diagnosed as chronic lymphocytic leukemia or non-Hodgkin lymphoma, also had the provirus genome in their tumor cells, whereas some cases with the same diagnosis did not. No cases of other types of lymphoma or leukemia contained the provirus genome in their tumor cells. Monoclonal integration of the HTLV provirus genome in all primary tumor cells of ATL not only indicates that HTLV directly interacts with target cells, which become leukemic, and that integration of the provirus genome is a prerequisite for development of ATL and possibly other related diseases but also indicates that the virus is not associated with other types of lymphoma or leukemia.Human retroviruses HTLV (human T-cell leukemia virus) (1-3) and ATLV (adult T-cell leukemia virus) (4, 5) were independently isolated from cases of cutaneous T-cell lymphoma (CTCL) and adult T-cell leukemia (ATL) (6), respectively. Subsequently, HTLV and ATLV were shown to be similar in immunological crossreactivities (7,8) and nucleic acid hybridization (9). Recently, we determined the total nucleotide sequence of the ATLV provirus genome (10) and showed that ATLV and HTLV type I are identical with respect to the locations of gene-specific sequences and the sites of some restriction enzymes (11). We use the term ATK strain of HTLV (HTLVATK) for the virus previously cloned in ATK-1 DNA and reported as ATLV (5, 10). The retrovirus HTLV is exogenous for humans (2, 5) and distinct from known animal retroviruses with respect to the structure of its provirus genome (10, 12). Furthermore, HTLV was shown to be closely associated with a unique T-cell malignancy, ATL, by extensive surveys of antibodies against the viral proteins (4, 7, 8, 13-15). The association of the virus with ATL was also shown by detecting the provirus genome in leukemic cells of ATL patients (5,16). Some patients with other types of lymphoma or leukemia, such as CTCL, chronic lymphocytic leukemia (T-CLL), and non-Hodgkin lymphoma of T-cell origin, were also reported to have antibodies against the viral proteins (4, 17). The presence of antibodies to viral proteins is evidence for infection with HTLV but does not provide any information on the mode of involvement of the virus in leukemogenesis.To understand whether HTLV is directly involved in leukemogenesis of ATL and whether the virus is associated with any other types of lymphomas or leukemias, we surveyed the provirus genome ...

Partial overlapping cDNA sequences likely to encode a novel human CC chemokine were identified from the GenBank Expressed Sequence Tag data base. Using these sequences, we isolated full-length cDNA encoding a protein of 96 amino acid residues with 20 -28% identity to other CC chemokines. By Northern blot, this chemokine was mainly expressed in liver among various tissues and strongly induced in several human cell lines by phorbol myristate acetate. We thus designated this chemokine as LARC from Liver and Activation-Regulated Chemokine. We mapped the LARC gene close to the chromosomal marker D2S159 at chromosome 2q33-q37 by somatic cell and radiation hybrid mappings and isolated two yeast artificial chromosome clones containing the LARC gene from this region. To prepare LARC, we subcloned the cDNA into a baculovirus vector and expressed it in insect cells. The secreted protein started at Ala-27 and was significantly chemotactic for lymphocytes. At a concentration of 1 g/ml, it also showed a weak chemotactic activity for granulocytes. Unlike other CC chemokines, however, LARC was not chemotactic for monocytic THP-1 cells or blood monocytes. LARC tagged with secreted alkaline phosphatase-(His) 6 bound specifically to lymphocytes, the binding being competed only by LARC and not by other CC or CXC chemokines. Scatchard analysis revealed a single class of receptors for LARC on lymphocytes with a K d of 0.4 nM and 2100 sites/cell. Collectively, LARC is a novel CC chemokine, which may represent a new group of CC chemokines localized on chromosome 2.

No abstract

Summary. This phase II trial was performed to evaluate the efficacy of a new granulocyte colony-stimulating factor (G-CSF)-supported multi-agent chemotherapy protocol, LSG15, for aggressive adult T-cell leukaemia-lymphoma (ATL). Ninety-six previously untreated patients with aggressive ATL were enrolled and grouped as: acute type (58), lymphoma type (28) and unfavourable chronic type (10). Therapy consisted of seven cycles of VCAP (vincristine, cyclophosphamide, doxorubicin and prednisone), AMP (doxorubicin, ranimustine and prednisone) and VECP (vindesine, etoposide, carboplatin and prednisone). G-CSF was administered during the intervals between chemotherapy until neutrophil reconstitution was achieved. Eighty-one per cent of the 93 eligible patients responded [95% confidence interval (CI), 71´1±88´1%], with 33 patients obtaining complete response (35´5%) and 42 obtaining partial response (45´2%). The median survival time (MST) after registration was 13 months and the median follow-up duration of the 20 surviving patients was 4´2 years (range 2´8±5´6). Overall survival at 2 years was estimated to be 31´3% (95% CI, 22´0±40´5%). Grade 4 haematological toxicity of neutropenia and thrombocytopenia were observed in 65´3% and 52´6% of the patients respectively, but grade 4 non-haematological toxicity was observed in only one patient. LSG15 is feasible with mild non-haematological toxicity and improved the clinical outcome of ATL patients. MST and overall survival at 2 years were superior to those obtained by our previous trials.