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A novel subclonal rearrangement of the STRN3::PDGFRB gene in de novo acute myeloid leukemia with NPM1 mutation and its leukemogenic effects

Cancer Gene Therapy volume 30, pages 1471–1484 (2023)Cite this article

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Abstract

Chromosome translocations in the 5q31-33 region are associated with a range of hematologic malignancies, some of which involve the platelet-derived growth factor receptor beta (PDGFRB) gene. We report a case of acute myeloid leukemia (AML) with a mutation in the NPM1 gene (NPM1-mut AML) and a subclonal gene rearrangement involving the PDGFRB gene. We identified a novel fusion gene, STRN3::PDGFRB, resulting from t(5;14) (q32;q12) chromosomal rearrangement. Sequential FISH confirmed that ~15% of leukemic cells carried the PDGFRB gene rearrangement, which suggests that STRN3::PDGFRB is a previously unreported fusion gene in a subclone. Reverse transcription PCR (RT-PCR) and Sanger sequencing confirmed that the fusion gene consisted of STRN3 exon 7 fused to PDGFRB exon 11, resulting in a chimeric protein containing the coiled-coil domain of striatin-3 and the transmembrane and intracellular tyrosine kinase domains of the PDGFRB. The new protein exhibited distinct cytoplasmic localization and had leukemogenic effects, as demonstrated by its ability to transform Ba/F3 cells to growth factor independence and cause a fatal myelodysplastic/myeloproliferative neoplasm (MDS/MPN)-like disease in mice, which then transformant to T-cell lymphoblastic lymphoma in secondary recipients. Ba/F3 cells expressing STRN3::PDGFRB or ETV6::PDGFRB were sensitive to tyrosine kinase inhibitors (TKIs) and selinexor, but in vitro experiments showed that the combination of imatinib and selinexor had a marked synergistic effect, although only the imatinib alone group could prolong the survival of T-cell blast transformation recipient mice. Our findings demonstrate the leukemogenic effects of the novel fusion gene and provide insights into the clone evolution of AML, which can be influenced by therapy selection. Furthermore, our results provide insight into the potential therapeutic options for patients with this type of mutation, as well as the need for careful consideration of treatment selection to prevent undesirable side effects.

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Fig. 1: Laboratory data of the patient.
Fig. 2: The translocations involving STRN3 and PDGFRB breakpoints.
Fig. 3: Clonal architecture of this patient.
Fig. 4: Oncogenic properties of STRN3::PDGFRB.
Fig. 5: In vivo transforming activity of STRN3::PDGFRB.
Fig. 6: The secondary recipients developed T lymphoblastic lymphoma.
Fig. 7: Effects of TKIs or XOP1 inhibitors in vitro and in vivo.

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Data availability

The main data supporting the results of this study are available within the article and supplementary materials.

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Acknowledgements

This work was supported by grant 82270190 from the National Natural Science Foundation of China (NSFC); grant 2019YFC0840605 from the National Key Research and Development Program of China.

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  1. State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, 288 Nanjing Road, Tianjin, 300020, China

    Zhe Wang, Ting Liu, Wenbing Liu, Xin Gao, Li Wan, Shaowei Qiu, Yang Song, Runxia Gu, Zheng Tian, Min Wang, Jianxiang Wang, Yingchang Mi & Shuning Wei

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Contributions

ZW: Conceptualization, resources, data curation, formal analysis, validation, investigation, and writing-original draft. TL: Data curation, formal analysis, validation, and investigation. WL: Data curation and formal analysis. LW: Validation and investigation. XG: Data curation, validation, and investigation. SQ: Data curation and formal analysis. YS: Resources and investigation. ZT: Data curation and formal analysis. MW: Resources, formal analysis, and investigation. JW: Resources and supervision. YM: Conceptualization, supervision, funding acquisition, writing—review, and editing. SW: Resources and supervision.

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Correspondence to Yingchang Mi or Shuning Wei.

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Wang, Z., Liu, T., Liu, W. et al. A novel subclonal rearrangement of the STRN3::PDGFRB gene in de novo acute myeloid leukemia with NPM1 mutation and its leukemogenic effects. Cancer Gene Ther 30, 1471–1484 (2023). https://doi.org/10.1038/s41417-023-00651-w

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