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CDK2 inhibition promotes neuronal differentiation in neuroblastoma
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  • Published: 06 February 2026

CDK2 inhibition promotes neuronal differentiation in neuroblastoma

  • Mohammad Alzrigat1 na1,
  • Loay Mahmoud2 na1,
  • Ada Nursel Topçu1 nAff4,
  • Marta Valenti1 nAff5,
  • Lu Zhang3,
  • Puck Veen1,
  • Fabian John1,
  • Wesam Bazzar3,
  • Kaisa Lehti2 &
  • …
  • Lars-Gunnar Larsson1,3 

Scientific Reports , Article number:  (2026) Cite this article

We are providing an unedited version of this manuscript to give early access to its findings. Before final publication, the manuscript will undergo further editing. Please note there may be errors present which affect the content, and all legal disclaimers apply.

Subjects

  • Cancer
  • Oncology

Abstract

Neuroblastoma (NB) is a childhood tumor arising from neural crest-derived progenitor cells. Cyclin dependent kinase 2 (CDK2) has been suggested to be a promising therapeutic target in NB especially MYCN-amplified tumors. How CDK2 contributes to the development of NB is not fully understood. Here, we demonstrate that high CDK2 expression in NB correlates with advanced and high-risk disease, MYCN-amplification, poor prognosis, and undifferentiated tumors. We uncovered that CDK2 genetic or pharmacological inhibition induces neuronal differentiation in human NB cell lines, which effect is in general more prominent in the MYCN-amplified subtype. Further, we establish CDK2 as a MYCN target gene that modulate the MYC-pathway in MYCN-amplified NB. Notably, pharmacological inhibition of CDK2 in combination with MYCN inhibition or all-trans-retinoic acid (ATRA) differentiation therapy enhances neuronal differentiation in vitro. These results reveal an important function of CDK2 in NB and highlight CDK2 inhibition alone or in combination with MYC inhibitors and retinoids as a potential strategy for differentiation therapy in NB.

Data availability

The NB primary tumor gene expression datasets: the SEQC-498, Westermann-579, Kocak-649, and TARGET-161 analyzed during the current study are available in the R2: Genomics Analysis and Visualization Platform repository ([http://r2.amc.nl](http:/r2.amc.nl)). The gene expression dataset following CDK2-KD in the MYCN-amplified cell line IMR32 is available at gene expression omnibus under the accession number GSE16480. The single cell RNA-seq data is available at NB atlas (https://single-cell.be/nbatlas/). No datasets were generated in this study.

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Acknowledgements

The authors express their great gratitude to all funding agencies, biomedicum imaging core facility and the biomedicum common virus laboratory BSL-2 at the Karolinska Institutet.

Funding

Open access funding provided by Karolinska Institute. This work was supported by grants from the Swedish Childhood Cancer Foundation (Barncancerfonden) (MA & LGL), O. E. och Edla Johanssons vetenskapliga stiftelse (MA), Stiftelsen Lars Hiertas Minne (MA), Fredrik och Ingrid Thurings Stiftelse (MA), and Lillian Sagens och Curt Ericssons Forskningsstiftelse (MA), The Swedish Cancer Foundation (Cancerfonden) (LGL), NovoNordisk Foundation (LGL), MyCural Therapeutics AB (LGL) and the Norwegian Cancer Society (216113, KL).

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Author notes

  1. Ada Nursel Topçu

    Present address: Institute for Neuroscience and Cardiovascular Research, The University of Edinburgh, Edinburgh, UK

  2. Marta Valenti

    Present address: Centre for Regenerative Medicine “Stefano Ferrari”, Department of Life Science, University of Modena and Reggio Emilia, Modena, Italy

  3. These authors contributed equally: Mohammad Alzrigat and Loay Mahmoud.

Authors and Affiliations

  1. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Solna, Stockholm, Sweden

    Mohammad Alzrigat, Ada Nursel Topçu, Marta Valenti, Puck Veen, Fabian John & Lars-Gunnar Larsson

  2. Department of Chemistry and Biomedical Science, Faculty of Natural Sciences, Norwegian University of Science and Technology, Trondheim, Norway

    Loay Mahmoud & Kaisa Lehti

  3. Department of Pharmaceutical Biosciences, Uppsala Biomedical Centre, Uppsala University, Uppsala, Sweden

    Lu Zhang, Wesam Bazzar & Lars-Gunnar Larsson

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Contributions

MA and LGL conceptualized and supervised the study, acquired funding, and wrote the manuscript. MA, LM, ANT, MV, LZ, PV, FJ, and WB performed experiments, analyzed, interpreted, and visualized the data. KL provided resources, supervision of LM, analyzed and interpreted the data. All authors have read and approved the final draft of the manuscript.

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Correspondence to Mohammad Alzrigat.

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LGL is cofounder of MyCural Therapeutics AB and has ownership interests (including patents) in this company.

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Alzrigat, M., Mahmoud, L., Topçu, A.N. et al. CDK2 inhibition promotes neuronal differentiation in neuroblastoma. Sci Rep (2026). https://doi.org/10.1038/s41598-026-38123-4

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  • Received: 24 May 2025

  • Accepted: 29 January 2026

  • Published: 06 February 2026

  • DOI: https://doi.org/10.1038/s41598-026-38123-4

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Keywords

  • Neuroblastoma
  • CDK2
  • Neuronal differentiation
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