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Originally published online as doi:10.2353/ajpath.2007.060934 on June 14, 2007

Published online before print June 14, 2007
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(American Journal of Pathology. 2007;171:654-666.)
© 2007 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2007.060934

SET-CAN, the Product of the t(9;9) in Acute Undifferentiated Leukemia, Causes Expansion of Early Hematopoietic Progenitors and Hyperproliferation of Stomach Mucosa in Transgenic Mice

Ugur Özbek*, Ayten Kandilci*, Sjozef van Baal*{dagger}, Jacqueline Bonten*, Kelli Boyd{ddagger}, Patrick Franken*{dagger}, Riccardo Fodde{dagger} and Gerard C. Grosveld*{ddagger}

From the Department of Genetics and Tumor Cell Biology* and Animal Resource Center,{ddagger} St. Jude Children’s Research Hospital, Memphis, Tennessee; and the Department of Pathology,{dagger} Josephine Nefkens Institute, Erasmus University Medical Center, Rotterdam, The Netherlands

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-D3-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 ß-catenin and vastly increased numbers of proliferating gastric mucosa cells, suggesting a role of SET-CAN in proliferation of certain epithelial cells.




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[Abstract] [Full Text] [PDF]


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Copyright © 2007 by the American Society for Investigative Pathology.