ORIGINAL PAPER

Prognostic impact of FLT3-ITD mutation on NPM1⁺ acute myeloid leukaemia patients and related molecular mechanisms

Xin’an Pan

National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University Institute of Hematology, Peking University People's Hospital, Beijing, China

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Yingjun Chang,

Yingjun Chang

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Guorui Ruan,

Guorui Ruan

orcid.org/0000-0001-7832-9234

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Fangfang Wei,

Fangfang Wei

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Hao Jiang,

Hao Jiang

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Qian Jiang,

Qian Jiang

orcid.org/0000-0001-7131-0522

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Xiaojun Huang,

Xiaojun Huang

Peking-Tsinghua Center for Life Sciences, Beijing, China

Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, Beijing, China

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Xiaosu Zhao,

Corresponding Author

Xiaosu Zhao

[email protected]

orcid.org/0000-0001-7749-8087

Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, Beijing, China

Correspondence

Xiaosu Zhao, Peking University Institute of Hematology, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing 100 044, China.

Email: [email protected]

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Xin’an Pan,

Xin’an Pan

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Yingjun Chang,

Yingjun Chang

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Guorui Ruan,

Guorui Ruan

orcid.org/0000-0001-7832-9234

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Fangfang Wei,

Fangfang Wei

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Hao Jiang,

Hao Jiang

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Qian Jiang,

Qian Jiang

orcid.org/0000-0001-7131-0522

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Xiaojun Huang,

Xiaojun Huang

Peking-Tsinghua Center for Life Sciences, Beijing, China

Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, Beijing, China

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Xiaosu Zhao,

Corresponding Author

Xiaosu Zhao

[email protected]

orcid.org/0000-0001-7749-8087

Research Unit of Key Technique for Diagnosis and Treatments of Hematologic Malignancies, Chinese Academy of Medical Sciences, Beijing, China

Correspondence

Xiaosu Zhao, Peking University Institute of Hematology, Peking University People's Hospital, No. 11 Xizhimen South Street, Beijing 100 044, China.

Email: [email protected]

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First published: 25 August 2023

https://doi.org/10.1111/bjh.18973

Citations: 1

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Summary

The prognosis of acute myeloid leukaemia (AML) patients carrying NPM1 mutations is significantly worse when accompanied by FLT3-ITD mutations. However, accurate quantitative detection of FLT3-ITD mutations remains challenging. To identify a novel biomarker in NPM1⁺FLT3-ITD⁺ AML patients for more accurate stratification, we analysed the differential gene expression between the NPM1⁺FLT3-ITD⁺ and NPM1⁺FLT3-ITD⁻ groups in five public AML datasets and identified a biomarker by taking the intersection of differentially expressed genes. We validated this biomarker in bone marrow samples from NPM1⁺ AML patients at the Peking University Institute of Haematology and analysed its prognostic significance. BCAT1 expression was higher in the NPM1⁺FLT3-ITD⁺ group than in the NPM1⁺FLT3-ITD⁻ group in all seven cohorts. BCAT1 was able to predict the prognosis of NPM1⁺FLT3-ITD⁺ AML patients, and its predictive ability was superior to that of the FLT3-ITD allelic ratio (AR). FLT3-targeted inhibitor quizartinib reduced BCAT1 expression. BCAT1 knockdown using lentiviral vectors led to the downregulation of MYC expression. Thus, we identified BCAT1 as a novel biomarker for NPM1⁺FLT3-ITD⁺ AML patients. The FLT3-ITD/BCAT1/MYC signalling pathway may play a biological role in promoting the occurrence and development of AML in FLT3-ITD⁺ cell lines.

Graphical Abstract

Due to mutations in exon 12 of NPM1, the C-terminal nuclear localization signal (NoLs) is disrupted, leading to the formation of a novel nuclear export signal (NES). Exportin 1 interacts with NPM1c⁺ carrying NES and facilitates its transportation into the cytoplasm. The FLT3-ITD mutation leads to elevated expression of BCAT1, subsequently upregulating the expression of the MYC gene, thereby exerting biological functions that promote the occurrence and development of AML.

CONFLICT OF INTEREST STATEMENT

The authors declare that they have no known conflicting financial interests or personal relationships that could appear to have influenced the work presented in this paper.

Open Research

DATA AVAILABILITY STATEMENT

The datasets generated and/or analysed during the present study are available from the corresponding author upon reasonable request.

Supporting Information

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Volume203, Issue2

October 2023

Pages 212-223

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Prognostic impact of FLT3-ITD mutation on NPM1⁺ acute myeloid leukaemia patients and related molecular mechanisms

Summary

Graphical Abstract

CONFLICT OF INTEREST STATEMENT

Open Research

DATA AVAILABILITY STATEMENT

Supporting Information

REFERENCES

Citing Literature

References

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Prognostic impact of FLT3-ITD mutation on NPM1+ acute myeloid leukaemia patients and related molecular mechanisms

Summary

Graphical Abstract

CONFLICT OF INTEREST STATEMENT

Open Research

DATA AVAILABILITY STATEMENT

Supporting Information

REFERENCES

Citing Literature

References

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Prognostic impact of FLT3-ITD mutation on NPM1⁺ acute myeloid leukaemia patients and related molecular mechanisms