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Cytogenetics and molecular genetics

Exome sequencing identifies highly recurrent somatic GATA2 and CEBPA mutations in acute erythroid leukemia

Leukemia volume 31, pages 195–202 (2017)Cite this article

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Abstract

Acute erythroid leukemia (AEL), characterized by a predominant erythroid proliferation, is a subtype of acute myelogenous leukemia. The genetic basis of AEL remains poorly defined. Through whole-exome sequencing, we identified high frequencies of mutations in CEBPA (32.7%), GATA2 (22.4%), NPM1 (15.5%), SETBP1 (12.1%) and U2AF1 (12.1%). Structure prediction analysis revealed that most of the GATA2 mutations were located at the DNA-binding N-terminal zinc-finger near the DNA-binding interface, suggesting that mutations could result in at least partial inactivation of GATA2 protein. On co-transfection of a GATA-responsive reporter construct together with plasmids expressing either GATA2 wild-type or GATA2 ZF1 mutants (P304H, L321P and R330X) in 293T cells, we found a reduced transcriptional activation in cells transfected with GATA2 mutants. To determine whether reduced GATA2 function is involved in leukemogenesis of AEL, we transfected 32D cells with GATA2 mutants and evaluated the impact of GATA2 mutations on erythroid differentiation. Our data revealed an increased expression of erythroid-related antigens Ter-119, β-globin and βh1-globin, as well as increased hemoglobin positivity in 32D cells transfected with GATA2 mutants compared with control cells. Our results suggest that the decline of GATA2 resulting from mutations contributes to the erythroid commitment, differentiation and the development of AEL.

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Acknowledgements

This work was supported by grants from the Priority Academic Program Development of Jiangsu Higher Education Institutions, the Natural Science Foundation of China (81570139 and 81270617), Jiangsu Provincial Special Program of Medical Science (BL2012005), Jiangsu Province’s Key Medical Center (ZX201102), Jiangsu Province Natural Science Foundation for Distinguished Young Scholars (BK2012006) and Jiangsu Province Natural Science Fund (BE2015639).

Author contributions

SC and DW were the principal investigators. NP, AS, QW, JY, WC, YX, LW, HY, HQ and LM performed most of the experiments. SC, CR, YS and DW wrote the manuscript.

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Author notes

  1. N Ping, A Sun, Y Song and Q Wang: These four authors contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Jiangsu Institute of Hematology, Key Laboratory of Thrombosis and Hemostasis of Ministry of Health, The First Affiliated Hospital of Soochow University, Suzhou, PRC

    N Ping, A Sun, Q Wang, J Yin, W Cheng, Y Xu, L Wen, H Yao, L Ma, H Qiu, C Ruan, D Wu & S Chen

  2. Collaborative Innovation Center of Hematology, Soochow University, Suzhou, PRC

    A Sun, H Qiu, C Ruan, D Wu & S Chen

  3. Cyrus Tang Hematology Center, Jiangsu Institute of Hematology, Soochow University, Suzhou, PRC

    Y Song

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Correspondence to D Wu or S Chen.

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Ping, N., Sun, A., Song, Y. et al. Exome sequencing identifies highly recurrent somatic GATA2 and CEBPA mutations in acute erythroid leukemia. Leukemia 31, 195–202 (2017). https://doi.org/10.1038/leu.2016.162

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  • DOI: https://doi.org/10.1038/leu.2016.162

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