Aberrant intracellular localization of SET-CAN fusion protein, associated with a leukemia, disorganizes nuclear export.

ABSTRACT

The SET-CAN fusion gene is the product of a chromosomal rearrangement found on 9q34 associated with an acute undifferentiated leukemia. SET-CAN encodes an almost complete SET protein fused to the C-terminal two-thirds of CAN. SET is also known as TAF-Ibeta, a histone chaperone and intracellular inhibitor of protein phosphatase 2A, whereas CAN is identical to Nup214, a nucleoporin protein. To obtain insight into the leukemogenic function of SET/TAF-Ibeta-CAN/Nup214, we have examined its subcellular localization. Immunofluorescence analyses showed that SET/TAF-Ibeta and CAN/Nup214 are found in the nucleus and the nuclear envelope, respectively, whereas the majority of SET/TAF-Ibeta-CAN/Nup214 is localized in the nucleus. SET/TAF-Ibeta-CAN/Nup214 interacted with hCRM1, one of the nuclear export factors, and caused aberrant intracellular localization of hCRM1. In cells expressing SET/TAF-Ibeta-CAN/Nup214, a protein containing a nuclear export signal accumulated in the nucleus. The export of this protein was partially restored by overexpression of hCRM1. These results suggest that aberrantly localized molecules associated with SET/TAF-Ibeta-CAN/Nup214 may be involved in oncogenesis.