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ACUTE MYELOID LEUKEMIA

A novel gene fusion RUNX1/ZNF423 promotes leukemic relapse of NUP98-rearranged AML

Leukemia volume 37, pages 2286–2291 (2023)Cite this article

Subjects

Oncogenic translocations involving NUP98 define a molecular subgroup of AML patients with dismal prognosis and higher incidence of relapse, which detected in 3.8% of pediatric AML and 0.7% of adult AML [1,2,3,4]. The lack of molecular biomarkers predicting further disease progression and final outcome impeded the development of precise diagnosis and therapeutic for NUP98-rearranged AML subgroup. Although the molecular process involving in NUP98-fusion-driven leukemogenesis has been uncovered, the underlying reasons for a high probability of relapse and unfavorable clinical outcome are still remain unknown. Genetic heterogeneity has been associated to AML clinical outcome [2]. Wherein many novel gene fusions have been identified in AML patients with abnormal chromosome structures, which might be responsible for aggressive progression and relapse [5,6,7]. Functional research is required to understand the associations of these newly-found gene translocations with poor long-term outcomes, which could provide deep molecular insights into the causes of AML relapse.

Then we tried to determine the reproducibility of the patient’s disease as well as the complicated characteristics of gene fusions on PDX model. NSG mice were intravenously transplanted with leukemic cells separated from BM aspirates from the patient, subsequently monitoring the leukemic burden and survival time of mice. Besides, the primary samples bearing NUP98/NSD1 + FLT3-ITD as well as other AML without NUP98 fusions were introduced as controls (Fig. 1G and Supplementary Tables 1–2). Abundant engraftment level was detected in BM of NUP98/NSD1 + RUNX1/ZNF423 + FLT3-ITD group rather than NUP98/NSD1 + FLT3-ITD group or other AML group (Fig. 1H) as well as peripheral blood and spleen (Supplementary Fig. 2). Besides, the existence of both gene fusions, NUP98/NSD1 and RUNX1/ZNF423, in BM blasts obtained from PDXs were still obviously detected (Fig. 1I). Finally, NUP98/NSD1 + RUNX1/ZNF423 + FLT3-ITD group presented significantly poorer survival than mice transplanted with NUP98/NSD1 + FLT3-ITD or other AML group (Fig. 1J). Overall, RUNX1/ZNF423 oncofusion assists to increase the engraftment of NUP98-rearranged AML blasts.

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Fig. 1: A novel fusion RUNX1/ZNF423 in a case of relapse NUP98/NSD1+ AML displays aggressive leukemogenic potential.
Fig. 2: Additional gene fusions including RUNX1/ZNF423 cooperate with NUP98/NSD1 to promote leukemia relapse and chemoresistance.

Data availability

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request. And the datasets analyzed during the current study are available in the Therapeutically Applicable Research to Generate Effective Treatments (TARGET) portal (https://ocg.cancer.gov/programs/target).

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Funding

This study was supported by grants from the Nation Natural Science Foundation of China (No. 82273942 to XJS), the Natural Science Fund for Distinguished Young Scholars of Zhejiang Province (No. LR23H310001 to MDY) and the Fundamental Research Funds for the Central Universities.

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Authors and Affiliations

  1. Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 310058, Hangzhou, China

    Wenxin Du, Zhimei Xia, Shaowei Bing, Wei Wang, Xingya Zhang, Ji Cao, Bo Yang, Qiaojun He, Xuejing Shao & Meidan Ying

  2. Division of Hematology-Oncology, Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, 310052, Hangzhou, China

    Zebin Luo, Jingying Zhang, Xiaojun Xu & Meidan Ying

  3. Innovation Institute for Artificial Intelligence in Medicine, Zhejiang Provincial Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences and Alibaba-Zhejiang University Joint Research Center of Future Digital Healthcare, Zhejiang University, 310018, Hangzhou, China

    Yichang Chen & Zhan Zhou

  4. Engineering Research Center of Innovative Anticancer Drugs, Ministry of Education, 310000, Hangzhou, China

    Ji Cao, Bo Yang, Qiaojun He & Meidan Ying

  5. Cancer Center, Zhejiang University, 310058, Hangzhou, China

    Qiaojun He & Meidan Ying

Authors
  1. Wenxin Du
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Contributions

MDY, XJS, XJX and WXD conceived the study and analyzed data. ZBL, JYZ and XJX provided patients’ samples, collected the clinical information and performed the clinical treatment. WXD, ZMX and XYZ performed cell-based experiments. WXD, ZMX and WW performed animal studies. WXD, ZMX, SWB, YCC and ZZ performed analyses of database and sequencing data. JC, QJH and BY helped conceive the experiments. MDY, XJS and WXD wrote the paper.

Corresponding authors

Correspondence to Xuejing Shao, Xiaojun Xu or Meidan Ying.

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The authors declare no competing interests.

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Approval from the Institutional Research Ethics Committee of the hospital were obtained before the use of these clinical materials for research purposes. The Animal Research Committee at Zhejiang University approved all animal studies and animal care was provided in accordance with the institutional guidelines.

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Du, W., Xia, Z., Luo, Z. et al. A novel gene fusion RUNX1/ZNF423 promotes leukemic relapse of NUP98-rearranged AML. Leukemia 37, 2286–2291 (2023). https://doi.org/10.1038/s41375-023-02024-6

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