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ACUTE MYELOID LEUKEMIA

Loss of NOL10 leads to impaired disease progression of NUP98::DDX10 leukemia

Leukemia volume 39, pages 1368–1379 (2025)Cite this article

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Abstract

NUP98 rearrangements associated with acute myeloid leukemia and myelodysplastic syndromes generate NUP98-fusion proteins. One such fusion protein, NUP98::DDX10, contains the putative RNA helicase DDX10. The molecular mechanism by which NUP98::DDX10 induces leukemia is not well understood. Here, we show that 24 amino acids within the DDX10 moiety of NUP98::DDX10 are crucial for cell immortalization and leukemogenesis. NOL10, nucleolar protein 10, interacts with the 24 amino acids, and NOL10 is a critical dependency of NUP98::DDX10 leukemia development. Studies in a mouse model of NUP98::DDX10 leukemia showed that loss of Nol10 impaired disease progression and improved survival. We also identified a novel function of NOL10 in that it acts cooperatively with NUP98::DDX10 to regulate serine biosynthesis pathways and stabilize ATF4 mRNA. Collectively, these findings suggest that NOL10 is a critical regulator of NUP98::DDX10 leukemia and that targeting NOL10 (or the serine synthesis pathway regulated by NOL10) may be an effective therapeutic approach.

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Fig. 1: A 24 amino acid sequence within the C-terminal region of NUP98::DDX10 is required for immortalization of the cells.
Fig. 2: The 24 amino acid sequence within the C-terminal region of NUP98::DDX10 is essential for the development of leukemia.
Fig. 3: NOL10 interacts with NUP98::DDX10.
Fig. 4: NOL10 controls the expression of genes related to serine biosynthesis in NUP98::DDX10 leukemia cells.
Fig. 5: NUP98::DDX10 and NOL10 stabilize ATF4 mRNA.
Fig. 6: NUP98::DDX10 leukemia cells are dependent on the serine biosynthesis pathway.

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Data availability

The datasets generated and/or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Strambio-De-Castillia C, Niepel M, Rout MP. The nuclear pore complex: bridging nuclear transport and gene regulation. Nat Rev Mol Cell Biol. 2010;11:490–501.

    Article  CAS  PubMed  Google Scholar 

  2. Nakamura T, Largaespada D, Lee M, Johnson L, Ohyashiki K, Toyama K, et al. Fusion of the nucleoporin gene NUP98 to HOXA9 by the chromosome translocation t(7;11)(p15;p15) in human myeloid leukaemia. Nat Genet. 1996;12:154–8.

    Article  CAS  PubMed  Google Scholar 

  3. Brown J, Jawad M, Twigg SRF, Saracoglu K, Sauerbrey A, Thomas AE, et al. A cryptic t(5;11)(q35;p15.5) in 2 children with acute myeloid leukemia with apparently normal karyotypes, identified by a multiplex fluorescence in situ hybridization telomere assay. Blood. 2002;99:2526–31.

    Article  CAS  PubMed  Google Scholar 

  4. Arai Y, Hosoda F, Kobayashi H, Arai K, Hayashi Y, Kamada N, et al. The inv(11)(p15q22) chromosome translocation of de novo and therapy- related myeloid malignancies results in fusion of the nucleoporin gene, NUP98, with the putative RNA helicase gene, DDX10. Blood. 1997;89:3936–44.

    Article  CAS  PubMed  Google Scholar 

  5. Gough SM, Slape CI, Aplan PD. NUP98 gene fusions and hematopoietic malignancies: Common themes and new biologic insights. Blood. 2011;118:6247–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ahn JH, Davis ES, Daugird TA, Zhao S, Quiroga IY, Uryu H, et al. Phase separation drives aberrant chromatin looping and cancer development. Nature. 2021;595:591–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Xu H, Valerio DG, Eisold ME, Sinha A, Koche RP, Hu W, et al. NUP98 fusion proteins interact with the NSL and MLL1 complexes to drive leukemogenesis. Cancer Cell. 2016;30:863–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Shima Y, Yumoto M, Katsumoto T, Kitabayashi I. MLL is essential for NUP98-HOXA9-induced leukemia. Leukemia. 2017;31:2200–10.

    Article  CAS  PubMed  Google Scholar 

  9. Wang GG, Cai L, Pasillas MP, Kamps MP. NUP98-NSD1 links H3K36 methylation to Hox-A gene activation and leukaemogenesis. Nat Cell Biol. 2007;9:804–12.

    Article  CAS  PubMed  Google Scholar 

  10. Bammert L, Jonas S, Ungricht R, Kutay U. Human AATF/Che-1 forms a nucleolar protein complex with NGDN and NOL10 required for 40S ribosomal subunit synthesis. Nucleic Acids Res. 2016;44:9803–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Jin X, Tanaka H, Jin M, Fujita K, Homma H, Inotsume M, et al. PQBP5/NOL10 maintains and anchors the nucleolus under physiological and osmotic stress conditions. Nat Commun. 2023;14:1–5.

    PubMed  PubMed Central  Google Scholar 

  12. Shima Y, Honma Y, Kitabayashi I. PML-RARα and its phosphorylation regulate PML oligomerization and HIPK2 stability. Cancer Res. 2013;73:4278–88.

    Article  CAS  PubMed  Google Scholar 

  13. Xu S, Powers MA. Nup98-homeodomain fusions interact with endogenous Nup98 during interphase and localize to kinetochores and chromosome arms during mitosis. Mol Biol Cell. 2010;21:1585–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Schmoellerl J, Barbosa IAM, Eder T, Brandstoetter T, Schmidt L, Maurer B, et al. CDK6 is an essential direct target of NUP98 fusion proteins in acute myeloid leukemia. Blood. 2020;136:387–400.

    Article  PubMed  Google Scholar 

  15. Jevtic Z, Matafora V, Casagrande C, Santoro F, Minucci S, Garré M, et al. SMARCA5 interacts with NUP98-NSD1 oncofusion protein and sustains hematopoietic cells transformation. J Exp Clin Cancer Res. 2022;41:34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Terlecki-Zaniewicz S, Humer T, Eder T, Schmoellerl J, Heyes E, Manhart G, et al. Biomolecular condensation of NUP98 fusion proteins drives leukemogenic gene expression. Nat Struc Mol Biol. 2021;28:190–201.

    Article  CAS  Google Scholar 

  17. DeNicola GM, Chen PH, Mullarky E, Sudderth JA, Hu Z, Wu D, et al. NRF2 regulates serine biosynthesis in non-small cell lung cancer. Nat Genet. 2015;47:1475–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yang M, Vousden KH. Serine and one-carbon metabolism in cancer. Nat Rev Cancer. 2016;16:650–62.

    Article  CAS  PubMed  Google Scholar 

  19. Mattaini KR, Sullivan MR, Vander Heiden MG. The importance of serine metabolism in cancer. J Cell Biol. 2016;214:249–57.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang B, Zhang L, Dai T, Qin Z, Lu H, Zhang L, et al. Liquid–liquid phase separation in human health and diseases. Signal Transduct Target Ther. 2021;6:290.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Boija A, Klein IA, Sabari BR, Dall’Agnese A, Coffey EL, Zamudio AV, et al. Transcription factors activate genes through the phase-separation capacity of their activation domains. Cell. 2018;175:1842–55.

    Article  CAS  PubMed  Google Scholar 

  22. Jensen K, Shiels C, Freemont PS. PML protein isoforms and the RBCC/TRIM motif. Oncogene. 2001;20:7223–33.

    Article  CAS  PubMed  Google Scholar 

  23. Takahashi Y, Lallemand-Breitenbach V, Zhu J, de Thé H. PML nuclear bodies and apoptosis. Oncogene. 2004;23:2819–24.

    Article  CAS  PubMed  Google Scholar 

  24. Nguyen LA, Pandolfi PP, Aikawa Y, Tagata Y, Ohki M, Kitabayashi I. Physical and functional link of the leukemia-associated factors AML1 and PML. Blood. 2005;105:292–300.

    Article  CAS  PubMed  Google Scholar 

  25. Davis JL, Fallon HJ, Morris HP. Two enzymes of serine metabolism in rat liver and hepatomas. Cancer Res. 1970;30:2917–20.

    CAS  PubMed  Google Scholar 

  26. Snell K. Enzymes of serine metabolism in normal, developing and neoplastic rat tissues. Adv Enzym Regul. 1984;22:325–400.

    Article  CAS  Google Scholar 

  27. Pollari S, Käkönen SM, Edgren H, Wolf M, Kohonen P, Sara H, et al. Enhanced serine production by bone metastatic breast cancer cells stimulates osteoclastogenesis. Breast Cancer Res Treat. 2011;125:421–30.

    Article  CAS  PubMed  Google Scholar 

  28. Liu J, Guo S, Li Q, Yang L, Xia Z, Zhang L, et al. Phosphoglycerate dehydrogenase induces glioma cells proliferation and invasion by stabilizing forkhead box M1. J Neurooncol. 2013;111:245–55.

    Article  CAS  PubMed  Google Scholar 

  29. Tajan M, Hennequart M, Cheung EC, Zani F, Hock AK, Legrave N, et al. Serine synthesis pathway inhibition cooperates with dietary serine and glycine limitation for cancer therapy. Nat Commun. 2021;12:1–16.

    Article  Google Scholar 

  30. Allen RW, Moskowitz M. Arrest of cell growth in the G1 phase of the cell cycle by serine deprivation. Exp Cell Res. 1978;116:127–37.

    Article  CAS  PubMed  Google Scholar 

  31. Rowe PB, Sauer D, Fahey D, Craig G, McCairns E. One-carbon metabolism in lectin-activated human lymphocytes. Arch Biochem Biophys. 1985;236:277–88.

    Article  CAS  PubMed  Google Scholar 

  32. Davis SR, Stacpoole PW, Williamson J, Kick LS, Quinlivan EP, Coats BS, et al. Tracer-derived total and folate-dependent homocysteine remethylation and synthesis rates in humans indicate that serine is the main one-carbon donor. Am J Physiol Endocrinol Metab. 2004;286:272–9.

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Acknowledgements

This study was supported by Project for Promotion of Cancer Research and Therapeutic Evolution (P-PROMOTE) from AMED.

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Authors and Affiliations

  1. Oncology Innovation Center (ONIC)/Center for Translational Research, Fujita Health University, Toyoake, Aichi, Japan

    Yutaka Shima, Kazutsune Yamagata, Yoko Kuroki, Yukiko Aikawa & Issay Kitabayashi

  2. Division of Hematological Malignancy, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan

    Yutaka Shima, Kazutsune Yamagata, Yoko Kuroki & Issay Kitabayashi

  3. Department of Peptidomics, Sasaki Institute, Chiyoda-ku, Tokyo, Japan

    Kazuki Sasaki

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  1. Yutaka Shima
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  2. Kazutsune Yamagata
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Contributions

YS and IK conceived and designed the experiments. YS, KY, YK, KS, and YA performed the experiments. YS and KY performed the bioinformatic analysis. YS, KY, YK, KS, and IK analyzed the data. YS, KS, and IK wrote the manuscript. All authors edited the manuscript.

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Correspondence to Issay Kitabayashi.

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Shima, Y., Yamagata, K., Kuroki, Y. et al. Loss of NOL10 leads to impaired disease progression of NUP98::DDX10 leukemia. Leukemia 39, 1368–1379 (2025). https://doi.org/10.1038/s41375-025-02607-5

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