Recent breakthroughs have shed light on why certain patients with FGFR1-driven leukaemia fail to respond to standard therapies. Researchers discovered that a truncated derivative of the fibroblast growth factor receptor-1, called tnFGFR1, promotes the development of stem cell-like leukaemia/lymphoma syndrome (SCLL). This variant is unique because it functions independently of the full-length receptor. Furthermore, tnFGFR1 displays a high level of resistance to traditional kinase inhibitors, making it a formidable challenge in clinical practice. Consequently, understanding its molecular interaction is critical for developing effective interventions.

A Direct Regulatory Role in FGFR1-driven Leukaemia

Unlike standard FGFR1 kinases, the truncated variant lacks a traditional deoxyribonucleic acid-binding motif. However, it compensates for this by recruiting specific binding partners. Specifically, studies show that tnFGFR1 forms a regulatory complex with the splicing factor SFPQ and the octamer-binding protein NONO. Consequently, this complex occupies the promoters of critical oncogenes like Myc, Flt3, and Kit. By directly regulating gene transcription, this protein assembly drives extensive genetic reprogramming. Moreover, knockdown of either SFPQ or NONO successfully prevents the activation of these target genes, highlighting their essential role in disease progression. Therefore, this mechanism bypasses the need for traditional kinase signaling pathways.

New Therapeutic Targets for FGFR1-driven Leukaemia

Identifying this transcription complex provides a novel pathway for therapeutic intervention. For instance, researchers tested the NONO inhibitor auranofin on tnFGFR1-transformed cells. In laboratory settings, auranofin effectively suppressed cell proliferation. Furthermore, in mouse models, the treatment successfully mitigated the progression of the disease. Consequently, targeting the tnFGFR1-SFPQ-NONO axis may offer a viable strategy for treating patients who are otherwise insensitive to kinase inhibitors. In addition, future clinical trials may investigate whether these inhibitors can overcome drug resistance in advanced stages of the disease. Thus, moving beyond kinase inhibition could redefine the standard of care for this patient population.

Frequently Asked Questions

How does tnFGFR1 differ from the full-length FGFR1 receptor?

While full-length FGFR1 acts as a membrane-bound kinase, the truncated variant tnFGFR1 localizes to the nucleus. It serves as a transcription regulator rather than a traditional signaling kinase, which renders it insensitive to many kinase inhibitors.

What role does the SFPQ/NONO complex play in this cancer?

The SFPQ and NONO proteins act as binding partners for tnFGFR1. Together, they form a complex that binds to gene promoters, such as Flt3 and Kit, to drive the transcription of genes necessary for leukemic cell growth.

Could auranofin be used to treat this type of leukaemia?

Yes, research indicates that auranofin acts as an inhibitor of the NONO protein. By disrupting the regulatory complex, it suppresses the growth of resistant leukemic cells in both in vitro and in vivo models.

Disclaimer: This content is for informational and educational purposes only. It is not intended as medical advice or a substitute for professional medical management. Refer to the latest local and national guidelines for clinical practice.

References

Cowell JK et al. An oncogenic, truncated FGFR1 variant cooperates with SPFQ/NONO to regulate gene transcription in FGFR1-driven leukaemia. Br J Haematol. 2026 Mar 14. doi: 10.1111/bjh.70426. PMID: 41830421.

Kim SJ et al. RNA-binding protein NONO contributes to cancer cell growth and confers drug resistance as a theranostic target in TNBC. Theranostics. 2020;10(18):7974-7992.

Cai B et al. A truncated derivative of FGFR1 kinase cooperates with FLT3 and KIT to transform hematopoietic stem cells in syndromic and de novo AML. Commun Biol. 2022;5(1):751.