Targeting the FBXL12-FANCD2 Pathway Disrupts Replication Stress Tolerance in MYCN-Driven Neuroblastoma

Abstract

MYCN amplification drives replication stress in high-risk neuroblastoma, yet how MYCN-amplified tumour cells tolerate this stress to sustain proliferation remains poorly understood. Here we show that FBXL12, an SCF ubiquitin ligase substrate receptor that targets the Fanconi anaemia protein FANCD2 for degradation at replication forks, as well as the broader Fanconi anaemia and replication stress transcriptional program are elevated in high-risk and MYCN-amplified neuroblastoma. High FBXL12 expression independently predicts poor survival across neuroblastoma patient cohorts. FBXL12 loss stabilizes FANCD2 on chromatin, elevates ATR-dependent replication stress signalling and DNA damage during S phase, and impairs proliferation of MYCN-amplified neuroblastoma cells in vitro and in vivo. Mechanistically, MYCN directly engages the FBXL12-FANCD2 complex and antagonises FBXL12-mediated degradation of FANCD2 at replication forks, revealing that the oncogenic driver of replication stress also actively preserves the chromatin-bound FANCD2 pool required to tolerate it. Beyond S phase, FBXL12 loss disrupts FANCD2-dependent mitotic DNA synthesis and transmits unresolved replication intermediates into daughter cells. FBXL12-deficient cells consequently show transcriptional activation of MYC target gene, ATR, and mTOR signalling programs, and this pathway-concordant state confers differential sensitivity to ATR, and mTOR-targeting compounds, nominating candidate therapeutic strategies for this disease subset. Together, these findings define a MYCN-FBXL12-FANCD2 axis as a clinically relevant vulnerability in high-risk neuroblastoma.

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BibTeX RIS

BibTeX

@misc{chou2026targeting,
  title = {{Targeting the FBXL12-FANCD2 Pathway Disrupts Replication Stress Tolerance in MYCN-Driven Neuroblastoma}},
  author = {J. Chou and A. Malyukova and A. S. Bordonaro and K. Dygon and L. Litzenburger and E. Dalani and J. Xiao and C. Tümmler and G. Mermelekas and J. Seniveratne and M. Paolino and J. Rantala and L. M. Orre and G. Marshall and J. I. Johnsen and M. Wickström and A. Brunner and O. Sangfelt},
  howpublished = {bioRxiv},
  year = {2026},
  month = aug,
  doi = {10.64898/2026.08.29.745966},
  url = {https://www.biorxiv.org/content/10.64898/2026.08.29.745966v1},
  note = {CC BY},
}

RIS

TY  - UNPB
TI  - Targeting the FBXL12-FANCD2 Pathway Disrupts Replication Stress Tolerance in MYCN-Driven Neuroblastoma
AU  - J. Chou
AU  - A. Malyukova
AU  - A. S. Bordonaro
AU  - K. Dygon
AU  - L. Litzenburger
AU  - E. Dalani
AU  - J. Xiao
AU  - C. Tümmler
AU  - G. Mermelekas
AU  - J. Seniveratne
AU  - M. Paolino
AU  - J. Rantala
AU  - L. M. Orre
AU  - G. Marshall
AU  - J. I. Johnsen
AU  - M. Wickström
AU  - A. Brunner
AU  - O. Sangfelt
PY  - 2026
DA  - 2026/08/29
PB  - bioRxiv
DO  - 10.64898/2026.08.29.745966
UR  - https://www.biorxiv.org/content/10.64898/2026.08.29.745966v1
AB  - MYCN amplification drives replication stress in high-risk neuroblastoma, yet how MYCN-amplified tumour cells tolerate this stress to sustain proliferation remains poorly understood. Here we show that FBXL12, an SCF ubiquitin ligase substrate receptor that targets the Fanconi anaemia protein FANCD2 for degradation at replication forks, as well as the broader Fanconi anaemia and replication stress transcriptional program are elevated in high-risk and MYCN-amplified neuroblastoma. High FBXL12 expression independently predicts poor survival across neuroblastoma patient cohorts. FBXL12 loss stabilizes FANCD2 on chromatin, elevates ATR-dependent replication stress signalling and DNA damage during S phase, and impairs proliferation of MYCN-amplified neuroblastoma cells in vitro and in vivo. Mechanistically, MYCN directly engages the FBXL12-FANCD2 complex and antagonises FBXL12-mediated degradation of FANCD2 at replication forks, revealing that the oncogenic driver of replication stress also actively preserves the chromatin-bound FANCD2 pool required to tolerate it. Beyond S phase, FBXL12 loss disrupts FANCD2-dependent mitotic DNA synthesis and transmits unresolved replication intermediates into daughter cells. FBXL12-deficient cells consequently show transcriptional activation of MYC target gene, ATR, and mTOR signalling programs, and this pathway-concordant state confers differential sensitivity to ATR, and mTOR-targeting compounds, nominating candidate therapeutic strategies for this disease subset. Together, these findings define a MYCN-FBXL12-FANCD2 axis as a clinically relevant vulnerability in high-risk neuroblastoma.
ER  -

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