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Gata2 deficiency delays leukemogenesis while contributing to aggressive leukemia phenotype in Cbfb-MYH11 knockin mice

Leukemia volume 34, pages 759–770 (2020)Cite this article

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Abstract

Inversion of chromosome 16 (inv(16)) generates a fusion gene CBFB-MYH11, which is a driver mutation for acute myeloid leukemia (AML). Gene expression profiling suggests that Gata2, a hematopoietic transcription factor, is a top upregulated gene in preleukemic Cbfb-MYH11 knockin mice and is expressed in human inv(16) AML. On the other hand, we have also identified recurrent monoallelic deletions of GATA2 in relapsed human CBF-AML patients. To clarify the role of Gata2 in leukemogenesis by Cbfb-MYH11, we generated conditional Cbfb-MYH11 knockin mice with Gata2 heterozygous knockout. Gata2 heterozygous knockout reduced abnormal myeloid progenitors, which are capable of inducing leukemia in the Cbfb-MYH11 mice. Consequently, Cbfb-MYH11 mice with Gata2 heterozygous knockout developed leukemia with longer latencies than those with intact Gata2. Interestingly, leukemic cells with Gata2 heterozygous knockout gained higher number of mutations and showed more aggressive phenotype in both primary and transplanted mice. Moreover, leukemic cells with Gata2 heterozygous knockout showed higher repopulating capacity in competitive transplantation experiments. In summary, reduction of Gata2 activity affects mutational dynamics of leukemia with delayed leukemia onset in Cbfb-MYH11 knockin mice, but paradoxically results in a more aggressive leukemia phenotype, which may be correlated with leukemia relapse or poor prognosis in human patients.

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Acknowledgements

The authors thank Stacy Anderson, Martha Kirby, Irene C. Ginty, Wendy Pridgen, NHGRI Transgenic Mouse Core and the National Institutes of Health (NIH) Intramural Sequencing Center for their technical help. Special thanks to Erica Bresciani and Hirotsugu Oda for scientific comments. This work used the computational resources of the NIH High Performance Computing Biowulf cluster (http://hpc.nih.gov).

Funding

This work was supported by the Intramural Research Programs of the National Human Genome Research Institute and National Cancer Institute, as well as a JSPS Oversea Research Fellowship (to S.S.).

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  1. Satoshi Saida

    Present address: Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan

Authors and Affiliations

  1. Oncogenesis and Development Section, Translational and Functional Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA

    Satoshi Saida, Tao Zhen, Erika Kim, Kai Yu, Guadalupe Lopez & Paul P. Liu

  2. Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, MD, USA

    Lisa J. McReynolds

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Contributions

S.S. designed and performed experiments, analyzed data, and wrote the paper; T.Z., and G.L. performed experiments; E.K. performed RNA sequencing and microarray data analysis; K.Y. performed analysis of whole exome sequencing; L.J.M. contributed Gata2 mouse model expertise; and P.P.L. designed the experiments, analyzed data, and wrote the paper.

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Correspondence to Paul P. Liu.

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Saida, S., Zhen, T., Kim, E. et al. Gata2 deficiency delays leukemogenesis while contributing to aggressive leukemia phenotype in Cbfb-MYH11 knockin mice. Leukemia 34, 759–770 (2020). https://doi.org/10.1038/s41375-019-0605-7

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