The role of newly cloned genes related to chromosome translocation on hematological differentiation and proliferation.

染色体易位已被证明在血液系统恶性肿瘤的发生中起重要作用。最近对11q13区的研究揭示了套细胞淋巴瘤的发病机制，11q23区的易位在不同类型的血液系统恶性肿瘤中反复出现。例如恶性淋巴瘤、急性早幼粒细胞白血病、婴儿白血病和化疗后发生的继发性白血病。关于11q13区域，我们通过对突变易位病例的PRAD1转录本和断裂点区域的分析，证明了bcl1与PRAD1/Cyclin D1基因的同源性。最近，我们制备了一种针对PRAD1/Cyclin D1产物的单抗5D4，并证明了与套细胞淋巴瘤(MCL)相关的特异性阳性核染色。对334例…血液病患者的免疫组织化学染色资料进行分析在39例MCL中，MCL预后最差。我们从11q23区域克隆并鉴定了这两个基因，分别命名为MLL和PCK/P54。关于MLL基因，它编码一个3969个氨基酸的多肽，与三胸果蝇同源，含有两个推测的DNA结合基序，由三个AT-挂钩基序和两个多个锌指结构域组成。在具有11q23易位的急性白血病中，几乎所有的断裂点都位于MLL基因的聚集区。建立了逆转录酶-聚合酶链式反应(RT-PCR)。敏感性研究表明，在10^4~10^5细胞中可以检测到一个含有嵌合mRNA的克隆。该方法为11q23易位白血病的诊断和疗效监测提供了一种快速、准确、灵敏的工具。我们最近对MLL基因的功能分析表明，该基因的N末端部分可能在肿瘤的发生和分化中发挥重要作用。此外，我们在实验室培育了MLL转基因小鼠，并对它们进行了一年半以上的观察。到目前为止，还没有观察到荷瘤小鼠。较少

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 … More 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