|Budget Amount *help
¥6,800,000 (Direct Cost : ¥6,800,000)
Fiscal Year 1995 : ¥1,400,000 (Direct Cost : ¥1,400,000)
Fiscal Year 1994 : ¥1,400,000 (Direct Cost : ¥1,400,000)
Fiscal Year 1993 : ¥4,000,000 (Direct Cost : ¥4,000,000)
Chromosome translocation has been demonstrated to play an important role in the genesis of hematopoietic malignancies. We focused the translocation involving the chromosome 11 band q13 and q23.
Recent studies of 11q13 region have shed light on the pathogenesis of mantle cell lymphoma and the translocation on region 11q23 has been recurrently observed in various types of hematopoietic malignancies. Such as malignant lymphoma, acute promyelocytic leukemia, infantile leukemia and secondary leukemia occurring after chemotherapy.
Regarding 11q13 region, we proved the identity between BCL-1 and the PRAD1/cyclin D1 gene based on our analyzes of the PRAD1 transcripts and the breakpoint region of the variant translocation case. Recently, we produced a monoclonal antibody, 5D4, against the PRAD1/cyclin D1 product and demonstrated specific positive nuclear staining to be associated with mantle cell lymphoma (MCL). According to the data of immunostaining obtained from 334 cases of hematological diso
rders including 39 cases of MCL,the MCL showed the poorest prognosis among them.
We cloned and characterize the two genes from the 11q23 region, and named MLL and PCK/P54 genes, respectively. Regarding MLL gene, which encodes a 3969 amino acid polypeptide homologous to Drosophila trithorax, containing two putative DNA-binding motifs consisting of three AT-hook motifs and two multiple zinc finger domains. Almost all the breakpoints in acute leukemia with 11q23 translocations lie in a cluster region on the MLL gene. We established the reverse trascriptase-polymerase chain reaction (RT-PCR). Sensitivity studies showed that a single clone with cheimeric mRNA in 10^4 to 10^5 cells could be detected. This RUT-PER method provide a rapid, accurate, and sensitive tool for diagnosing leukemia wtih 11q23 translocation and for monitoring response to therapy in these patients.
Recent our analyzes of function of MLL gene show the data thate the N-terminal portion of this gene, may play an important role on tumorigeneses and differentiation. Furthermore we produced the MLL transgenic mice in our laboratory, we have observed them more than one and half year. No tumor bearing mouse was observed, so far. Less