Ozbek Ugur, Kandilci Ayten, van Baal Sjozef, Bonten Jacqueline, Boyd Kelli, Franken Patrick, Fodde Riccardo, Grosveld Gerard C
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Am J Pathol. 2007 Aug;171(2):654-66. doi: 10.2353/ajpath.2007.060934. Epub 2007 Jun 14.
Leukemia-specific chromosome translocations involving the nucleoporin CAN/NUP214 lead to expression of different fusion genes including DEK-CAN, CAN-ABL, and SET-CAN. DEK-CAN and CAN-ABL1 are associated with acute myeloid leukemia and T-cell acute lymphoblastic leukemia, respectively, whereas SET-CAN was identified in a patient with acute undifferentiated leukemia. In addition, SET is overexpressed in solid tumors of the breast, uterus, stomach, and rectum. Ectopic expression of SET-CAN inhibits vitamin-D(3)-induced differentiation of the human promonocytic U937cells, whereas ectopic SET expression induces differentiation. Here, we assessed the leukemogenic potential of SET-CAN in the hematopoietic system of transgenic mice. Although SET-CAN mice showed expansion of an early progenitor cell pool and partial depletion of lymphocytes, the animals were not leukemia-prone and did not show shortening of disease latency after retroviral tagging. This suggests that SET-CAN expression in acute undifferentiated leukemia might determine the primitive phenotype of the disease, whereas secondary genetic lesions are necessary for disease development. Surprisingly, SET-CAN mice developed spontaneous hyperplasia of the stomach mucosa, which coincided with overexpression of beta-catenin and vastly increased numbers of proliferating gastric mucosa cells, suggesting a role of SET-CAN in proliferation of certain epithelial cells.
涉及核孔蛋白CAN/NUP214的白血病特异性染色体易位会导致包括DEK-CAN、CAN-ABL和SET-CAN在内的不同融合基因的表达。DEK-CAN和CAN-ABL1分别与急性髓性白血病和T细胞急性淋巴细胞白血病相关，而SET-CAN是在一名急性未分化白血病患者中发现的。此外，SET在乳腺癌、子宫癌、胃癌和直肠癌等实体瘤中过表达。SET-CAN的异位表达抑制维生素D(3)诱导的人原单核细胞U937细胞分化，而异位SET表达则诱导分化。在此，我们评估了SET-CAN在转基因小鼠造血系统中的致白血病潜力。尽管SET-CAN小鼠表现出早期祖细胞池的扩增和淋巴细胞的部分耗竭，但这些动物不易患白血病，并且在逆转录病毒标记后疾病潜伏期没有缩短。这表明急性未分化白血病中SET-CAN的表达可能决定了疾病的原始表型，而继发性遗传损伤对于疾病发展是必要的。令人惊讶的是，SET-CAN小鼠出现了胃黏膜的自发性增生，这与β-连环蛋白的过表达以及增殖的胃黏膜细胞数量大幅增加相一致，表明SET-CAN在某些上皮细胞的增殖中起作用。
