Fibroblast growth factor receptor 2 (FGFR2) is a potential activator of the MLL-AF4 leukemogenic protein.

The mixed-lineage leukemia (MLL) gene rearrangements are frequent in acute lymphoblastic leukemias. The t(4;11)(q21;q23) translocation fuses the 5′ portion of MLL to the 3′ portion of AF4 and leads to the synthesis of the chimeric oncoprotein, MLL-AF4. It mis-regulates the expression of MLL target genes that are implicated in cell differentiation and proliferation (HOXA9, MEIS1, p27kip1) (1). Indeed, the MLL-AF4–driven transactivation crucially depends on epigenetic modifications, e.g. H3-K79 methylation (1). However, there are also evidences that MLL-AF4 oncogenic pathways could involve some receptor tyrosine kinases (RTKs) (2). We previously demonstrated that, in HEK293 cells, both recombinant AF4 (Flag_AF4) and MLL-AF4 (Flag_MLL-AF4) interact with fibroblast growth factor receptor 2 (FGFR2) (4). Therefore, we further studied this interaction and demonstrated that it occurs in the nucleus, where both partners localize. We also confirmed that FGFR2 interacts with endogenous MLL-AF4 chimera, in RS4;11 lymphoblastic cells. Lastly, in HEK293 cells stably transfected with MLL-AF4, silencing of FGFR2 reduces HOXA9 transcript level. Our data strongly suggest that the oncogenic potential of MLL-AF4 chimera crucially depends on its nuclear interaction with FGFR2