The Nup98-HoxA9 Leukemogenic Fusion Protein Blocks Xpo1 and Tap-Mediated Nuclear Export

Abstract

Abstract 5228In leukemia Nup98 fusion genes are found as a product of the reciprocal translocation between Nucleoporin 98 (nup98) and homeobox-cluster genes. Nup98-HoxA9 (NHA9), the product of the t(7;11) translocation, is detected in acute myeloid leukemias (AMLs) and as a secondary abnormality in blast crisis of chronic myeloid leukemia (CML). The role of NHA9 in leukemogenesis is complex and incompletely understood. Here, we show an abrogation of nucleocytoplasmic shuttling of the nuclear export receptor Xpo1 and Tap in NHA9-expressing cells by using retroviral nuclear trafficking as a model. Lentiviral Rev, the prototype for nuclear export signal (NES)-containing proteins is shuttled through the nucleopore by Xpo1. NHA9 sequestered Xpo1 from the nuclear rim into nuclear aggregates resulting in deficient Xpo1-dependent nuclear exit of Rev and its mRNA substrates. Tap is involved in mRNA nucleocytoplasmic shuttling and is also responsible for the nuclear export of D-type retrovirus CTE-mRNAs. By using Tap/CTE-mRNA nuclear export as a model we also found that Tap colocalized in NHA9 nuclear aggregates leading to impaired Tap-mediated nuclear exit of CTE-mRNA substrates. Leukemogenicity of Nup98 fusion proteins may be accounted for in part by defects in Tap and Xpo1-mediated export of their substrates. Disclosures:No relevant conflicts of interest to declare.