An oncogenic, truncated FGFR1 variant cooperates with SPFQ/NONO to regulate gene transcription in FGFR1-driven leukaemia.

A truncated derivative of Fibroblast growth factor receptor-1 (FGFR1) (tnFGFR1) independently transforms haematopoietic stem cells leading to a stem cell-like leukaemia/lymphoma syndrome (SCLL). In mouse models, these transformed cells show extensive genetic reprogramming that is distinct from cells transformed with full-length chimeric FGFR1 kinases. We now show that the truncated derivative is insensitive to kinase inhibitors, and its increased expression is related to resistance to kinase inhibitors. Chromatin immunoprecipitation (ChIP) analysis shows that tnFGFR1 can occupy the promoters of the Myc, Flt3 and Kit genes suggesting a transcription regulatory function. However, without a deoxyribonucleic acid-binding motif, tnFGFR1 must interact with binding partners that supply this function. To define this potential regulatory complex, we performed immunoprecipitation-mass spectroscopy (IP-MS) and demonstrate that tnFGFR1 is present in a complex with the splicing factor proline- and glutamine-rich (SFPQ) protein and non-POU domain-containing octamer-binding protein (NONO) protein. In addition, this protein complex is present on the promoters of target genes Flt3 and Kit, and knockdown of either SFPQ or NONO prevents activation of their target genes. In addition, treatment with the NONO inhibitor auranofin suppresses cell proliferation of tnFGFR1-transformed cells in vitro mitigating leukaemia progression in vivo in a mouse model. Thus, future targeting of this tnFGFR1 transcription complex may provide a means for treating tnFGFR1-driven leukaemia.