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Chemotherapy targeting methylthioadenosine phosphorylase (MTAP) deficiency in adult T cell leukemia (ATL)

Leukemia volume 16, pages 1799–1807 (2002)Cite this article

Abstract

Methylthioadenosine phosphorylase (MTAP) is an important enzyme used for the salvage of adenine and methionine. Cells lacking this enzyme are expected to be sensitive to purine synthesis inhibitors and/or methionine starvation. We reported previously that the MTAP gene is deleted in adult T cell leukemia (ATL) cells. In the present study, we expanded our series and used a real-time quantitative PCR assay for accurate diagnosis of the deletion and nine of 65 primary ATL samples (13.8%) were MTAP negative. In spite of this low incidence, ATL cells showed significantly higher sensitivity to L-alanosine, an inhibitor of de novo adenosine monophosphate (AMP) synthesis, than normal lymphocytes, suggesting that the MTAP gene is inactivated not only by deletion but also by other mechanisms. Indeed, a real-time quantitative RT-PCR assay disclosed that primary ATL cells had significantly lower MTAP mRNA expression than normal lymphocytes. Since MTAP-negative ATL cell lines also showed much higher sensitivity to L-alanosine than MTAP-positive ATL cell lines, we used these cell lines to investigate whether it is possible to develop selective therapy targeting MTAP deficiency. A substrate of MTAP, methylthioadenosine (MTA) or its substitutes rescued concanavalin A (Con A)-activated normal lymphocyte proliferation from L-alanosine toxicity. All the compounds except 5′-deoxyadenosine, however, also caused the undesirable rescue of MTAP-negative ATL cell lines. 5′-Deoxyadenosine had the desired ability to rescue hematopoietic progenitor cells without rescuing ATL cell lines. These results support the rationale for a chemotherapy regimen of L-alanosine combined with 5′-deoxyadenosine rescue in MTAP-deficient ATL.

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Acknowledgements

We thank Mr K Nohda, Ms T Hayashi and Ms N Dateki for their technical assistance. This study was supported by JSPS Research Fellowships for Young Scientists (HH) and research grants (YY, 10670956) from the Japanese Ministry of Education, Culture, Sports, Science and Technology.

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Authors and Affiliations

  1. Department of Laboratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

    H Harasawa, Y Yamada, K Sugahara, H Soda, Y Hirakata & S Kamihira

  2. Department of Hospital Pharmacy, Nagasaki University Hospital, Nagasaki, Japan

    M Kudoh & H Sasaki

  3. Department of Blood Transfusion Service, Nagasaki University Hospital, Nagasaki, Japan

    T Matsuo

  4. Department of Hematology, Atomic Disease Institute, Nagasaki University School of Medicine, Nagasaki, Japan

    M Tomonaga

  5. Department of Internal Medicine, Sasebo General Hospital, Sasebo, Japan

    S Ikeda

  6. Department of Laboratory Medicine, Mie University School of Medicine, Mie, Japan

    T Nobori

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Harasawa, H., Yamada, Y., Kudoh, M. et al. Chemotherapy targeting methylthioadenosine phosphorylase (MTAP) deficiency in adult T cell leukemia (ATL). Leukemia 16, 1799–1807 (2002). https://doi.org/10.1038/sj.leu.2402570

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