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.
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.
Ozbek
Ugur
U
Department of Genetics and Tumor Cell Biology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Kandilci
Ayten
A
van Baal
Sjozef
S
Bonten
Jacqueline
J
Boyd
Kelli
K
Franken
Patrick
P
Fodde
Riccardo
R
Grosveld
Gerard C
GC
D000208:Acute Disease; D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D033481:Chromosomes, Mammalian / Q000235:genetics; D003114:Colony-Forming Units Assay; D005260:Female; D005434:Flow Cytometry; D005753:Gastric Mucosa / Q000737:chemistry / Q000378:metabolism / Q000473:pathology*; D006412:Hematopoietic Stem Cells / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D006965:Hyperplasia; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D007938:Leukemia / Q000097:blood / Q000235:genetics / Q000473:pathology*; D008214:Lymphocytes / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D028861:Nuclear Pore Complex Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D014178:Translocation, Genetic
D002868:Chromosomal Proteins, Non-Histone; D019394:Ki-67 Antigen; D028861:Nuclear Pore Complex Proteins; C490093:Nup214 protein, mouse; D015514:Oncogene Proteins, Fusion