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Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia

Oncogene volume 29, pages 1963–1975 (2010)Cite this article

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Abstract

E2A-hepatic leukemia factor (HLF) is a chimeric protein found in B-lineage acute lymphoblastic leukemia (ALL) with t(17;19). To analyze the leukemogenic process and to create model mice for t(17;19)-positive leukemia, we generated inducible knock-in (iKI) mice for E2A-HLF. Despite the induced expression of E2A-HLF in the hematopoietic tissues, no disease was developed during the long observation period, indicating that additional gene alterations are required to develop leukemia. To elucidate this process, E2A-HLF iKI and control littermates were subjected to retroviral insertional mutagenesis. Virus infection induced acute leukemias in E2A-HLF iKI mice with higher morbidity and mortality than in control mice. Inverse PCR detected three common integration sites specific for E2A-HLF iKI leukemic mice, which induced overexpression of zinc-finger transcription factors: g rowth f actor i ndependent 1 (Gfi1), zinc-finger protein subfamily 1A1 isoform a (Zfp1a1, also known as Ikaros) and zinc-finger protein 521 (Zfp521). Interestingly, tumors with Zfp521 integration exclusively showed B-lineage ALL, which corresponds to the phenotype of human t(17;19)-positive leukemia. In addition, ZNF521 (human counterpart of Zfp521) was found to be overexpressed in human leukemic cell lines harboring t(17;19). Moreover, both iKI for E2A-HLF and transgenic for Zfp521 mice frequently developed B-lineage ALL. These results indicate that a set of transcription factors promote leukemic transformation of E2A-HLF-expressing hematopoietic progenitors and suggest that aberrant expression of Zfp521/ZNF521 may be clinically relevant to t(17;19)-positive B-lineage ALL.

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Acknowledgements

We thank Yuki Sakai, Kayoko Hashimoto, Yuko Tsukawaki and Rika Tai, for the care of the mice and technical assistance, Dr Nobuaki Yoshida for E14 ES cells, Dr Søren Warming, Dr Neal G Copeland and Dr Nancy A Jenkins for mouse Zfp521 cDNA, Dr Koichi Ikuta for mouse TCRJβ probe, Dr Hirotaka Matsui for statistical analysis and Dr Takuro Nakamura for helpful discussion. This work was in part supported by a grant-in-aid from the Ministry of Education, Science and Culture of Japan, a grant-in-aid for Cancer Research from the Ministry of Health, Labour and Welfare of Japan (13-2), Takeda Science Foundation, Astellas Foundation for Research on Metabolic Disorders, the Japan Leukaemia Research Fund and Tsuchiya Foundation.

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Authors and Affiliations

  1. Department of Developmental Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima, Japan

    N Yamasaki, K Miyazaki, T Sasaki & H Honda

  2. Department of Molecular Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Minami-ku, Hiroshima, Japan

    A Nagamachi & T Inaba

  3. Leukemogenosis Section, Laboratory of Cellular Oncology, National Cancer Institute, NIH, Bethesda, MD, USA

    R Koller & L Wolff

  4. Department of Pathology, Tokyo Women's Medical University, Shinjuku-ku, Tokyo, Japan

    H Oda

  5. Department of Immunology, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima, Japan

    M Miyazaki

  6. Department of Allergy and Rheumatology, Faculty of Medicine, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan

    Z-i Honda

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  1. N Yamasaki
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Correspondence to H Honda.

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Authorship

Contribution: NY, Z-iH, TI and HH designed and performed the research and wrote the paper; HO centralized the pathological analysis; RK and LW generated the retrovirus; KM, MM and TS participated in the flow cytometric analysis; AN performed colony assays. All the authors checked the final version of the paper.

Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Yamasaki, N., Miyazaki, K., Nagamachi, A. et al. Identification of Zfp521/ZNF521 as a cooperative gene for E2A-HLF to develop acute B-lineage leukemia. Oncogene 29, 1963–1975 (2010). https://doi.org/10.1038/onc.2009.475

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