FASN Is Critical for Maintenance of NUP98 Fusion-Induced Leukemias

NUP98 is a component of the nuclear pore complex (NPC), which plays an important role in molecular traffic between the cytoplasm and the nucleus. The NUP98 gene is rearranged and fused to several partner genes, such as HOXA9 and DDX10, in acute myeloid leukemia and myelodysplastic syndromes and the leukemia with NUP98 rearrangement has a poor prognosis. The role of the NUP98 moiety of NUP98 fusion proteins is not well investigated. NUP98 has two Phe-Gly (FG) repeat domains, which are characteristic of the NPC proteins. To investigate the role of the NUP98 moiety of NUP98 fusion proteins, we purified the protein complexes formed with wild-type NUP98-HOXA9 and its mutants that lack the each FG repeat domain and looked for the proteins that interact with the NUP98 moiety. Mass spectrometry analysis identified that fatty acid synthase (FASN) interacted with the FG repeat domain of NUP98-HOXA9. These data suggest two possibilities. One is that NUP98-HOXA9 may affect the activity of FASN. The other is that FASN may affect activity of NUP98-HOXA9. To test the former possibility, we tested the effect of NUP98-HOXA9 on the activity of FASN in vitro, and we found that NUP98-HOXA9 reduced the FASN activity. FASN is known to be essential for cell growth. In fact, the colony formation of the NUP98-HOXA9-immortalized mouse myeloid stem/progenitor cells was inhibited by shRNA for FASN.　Because NUP98-HOXA9 reduced FASN activity, we hypothesized that FASN activity is low in NUP98 fusion gene-transformed cells and FASN inhibition selectively inhibits the colony formation of these cells. To test this hypothesis, we examined the effect of orlistat, which is the inhibitor of FASN on the colony formation. Orlistat strongly inhibited the colony formation of NUP98-HOXA9- and NUP98-DDX10-transformed cells, but it did not severely affect, the colony-forming activities of other fusion genes-transformed cells and normal progenitor cells. Other FASN inhibitors inhibited the colony formation of NUP98-HOXA9- and NUP98-DDX10-transformed cells. NUP98-HOXA9- and NUP98-DDX10 did not affect the expression level of FASN. The inhibition of FASN did not affect the expression of Hoxa genes and Meis1 gene, which are upregulated by NUP98 fusions. These results suggest that FASN activity is low but is essential for NUP98 fusion-mediated leukemia cells, and that FASN can be a therapeutic target for NUP98 fusion gene-mediated leukemia.