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Ink4a and Arf are crucial factors in the determination of the cell of origin and the therapeutic sensitivity of Myc-induced mouse lymphoid tumor

Oncogene volume 31, pages 2849–2861 (2012)Cite this article

Abstract

The cell of origin of tumors and the factors determining the cell of origin remain unclear. In this study, a mouse model of precursor B acute lymphoblastic leukemia/lymphoma (pre-B ALL/LBL) was established by retroviral transduction of Myc genes (N-Myc or c-Myc) into mouse bone marrow cells. Hematopoietic stem cells (HSCs) exhibited the highest susceptibility to N-Myc-induced pre-B ALL/LBL versus lymphoid progenitors, myeloid progenitors and committed progenitor B cells. N-Myc was able to induce pre-B ALL/LBL directly from progenitor B cells in the absence of Ink4a and Arf. Arf was expressed higher in progenitor B cells than Ink4a. In addition, N-Myc induced pre-B ALL/LBL from Arf−/− progenitor B cells suggesting that Arf has a predominant role in determining the cell of origin of pre-B ALL/LBL. Tumor cells derived from Ink4a/Arf−/− progenitor B cells exhibited a higher rate of proliferation and were more chemoresistant than those derived from wild-type HSCs. Furthermore, the Mdm2 inhibitor Nutlin-3 restored p53 and induced massive apoptosis in mouse pre-B ALL/LBL cells derived from Ink4a/Arf−/− cells and human B-ALL cell lines lacking Ink4a and Arf expression, suggesting that Mdm2 inhibition may be a novel therapeutic approach to the treatment of Ink4a/Arf−/− B-ALL/LBL, such as is frequently found in Ph+ ALL and relapsed ALL. Collectively, these findings indicate that Ink4a and Arf are critical determining factors of the cell of origin and the therapeutic sensitivity of Myc-induced lymphoid tumors.

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Acknowledgements

We thank I Ishimatsu, Y Hata and S Suzuki for technical assistance, K Arai for help in the preparation of the manuscript, CJ Sherr (St Jude Children's Research Hospital) for providing Arf−/− mice, Dr A Kenny (Memorial Sloan-Kettering Cancer Center) for providing the N-Myc cDNA, Dr T Kitamura (The University of Tokyo) for providing the retroviral vector pMXs-IG and Plat-E cells and Dr A Iwama (Chiba University) for providing the Bmi1 cDNA. This work was supported by grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (HS) and the US National Institutes of Health CA55164, CA136411 and CA100632 (MA).

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Authors and Affiliations

  1. Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo, Japan

    E Sugihara, T Shimizu, N Onishi, K Kai, J Ishizawa, N Hashimoto & H Saya

  2. Japan Science and Technology Agency, CREST, Tokyo, Japan

    E Sugihara, T Shimizu & H Saya

  3. Department of Leukemia, Section of Molecular Hematology and Therapy, MD Anderson Cancer Center, University of Texas, Houston, TX, USA

    K Kojima & M Andreeff

  4. Drug Discovery Research Laboratories, Kyowa Hakko Kirin Co., Ltd., Shizuoka, Japan

    K Nagata

  5. Department of Disease Model, Research Institute of Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

    H Honda

  6. Department of Immunology, Graduate School of Biosciences, Hiroshima University, Hiroshima, Japan

    M Kanno

  7. Nagahama Institute of Bio-Science and Technology, Shiga, Japan

    M Miwa

  8. Division of Hematopoiesis, Center for AIDS Research, Kumamoto University, Kumamoto, Japan

    S Okada

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  1. E Sugihara
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Correspondence to H Saya.

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Dr Andreeff’s work is supported by grants from the NIH and by Hoffmann-La Roche, Nutley, NJ.

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Sugihara, E., Shimizu, T., Kojima, K. et al. Ink4a and Arf are crucial factors in the determination of the cell of origin and the therapeutic sensitivity of Myc-induced mouse lymphoid tumor. Oncogene 31, 2849–2861 (2012). https://doi.org/10.1038/onc.2011.462

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