Joh T, Kagami Y, Yamamoto K, Segawa T, Takizawa J, Takahashi T, Ueda R, Seto M
Laboratory of Chemotherapy, Aichi Cancer Center Research Institute, Nagoya, Japan.
Oncogene. 1996 Nov 7;13(9):1945-53.
11q23 chromosome aberrations are frequently observed in infantile as well as therapy-related leukemias. The target gene at 11q23, MLL, is disrupted by the translocation and becomes fused to various translocation partner genes such as AF4/FEL, LTG9/AF9 and LTG19/ENL. The resulting chimeric mRNAs are fused in frame and have been predicted to encode leukemia-specific chimeric proteins. In the present study, we raised antibodies against MLL, LTG9 and LTG19 and demonstrated that MLL and chimeric MLL-LTG9 and MLL-LTG19 products are synthesized in vivo and are localized in the nuclei, using immunofluorescence and cell fractionation studies. The truncated N-terminal portion of the MLL product common to the various types of 11q23 translocation was also localized in the nuclei in a similar fashion. Murine 32Dc13 cells stably expressing the truncated N-terminal MLL protein exhibited an inhibition of differentiation and a growth advantage following stimulation by granulocyte-colony stimulating factor, although the IL-3 dependency was not significantly changed in comparison to the parental cells. These results suggest that the N-terminal portion common to various MLL-chimeric products plays an important role in leukemogenesis.
11q23染色体畸变在婴儿白血病以及治疗相关白血病中经常被观察到。位于11q23的靶基因MLL会因易位而被破坏，并与各种易位伙伴基因融合，如AF4/FEL、LTG9/AF9和LTG19/ENL。所产生的嵌合mRNA是框内融合的，并且预计会编码白血病特异性嵌合蛋白。在本研究中，我们制备了针对MLL、LTG9和LTG19的抗体，并通过免疫荧光和细胞分级分离研究证明，MLL以及嵌合的MLL-LTG9和MLL-LTG19产物在体内合成并定位于细胞核中。各种类型的11q23易位所共有的MLL产物的截短N端部分也以类似方式定位于细胞核中。稳定表达截短N端MLL蛋白的小鼠32Dc13细胞在粒细胞集落刺激因子刺激后表现出分化抑制和生长优势，尽管与亲代细胞相比，其对IL-3的依赖性没有显著变化。这些结果表明，各种MLL嵌合产物共有的N端部分在白血病发生中起重要作用。
