Chemotherapy targeting methylthioadenosine phosphorylase (MTAP) deficiency in adult T cell leukemia (ATL)
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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L-alanosine inhibits conversion of inosine monophosphate to AMP and shows selective toxicity towards MTAP-null cancer cells.
“L-alanosine inhibits conversion of inosine monophosphate (IMP) to AMP, and shows selective toxicity towards MTAP-null cancer cells (Batova et al., 1999; Efferth et al., 2003; Harasawa et al., 2002), but was found to be clinically ineffective in patients with advanced MTAP-deficient tumors in a Phase II trial (Kindler et al., 2009).”
From Targeting Metabolism for Cancer Therapy (2017) · cites this paper as Harasawa et al., 2002
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- Authors
- Harasawa, H., Yamada, Y., Kudoh, M., Sugahara, K., Soda, H., Hirakata, Y., Sasaki, H., Ikeda, S., Matsuo, T., Tomonaga, M., Nobori, T., & Kamihira, S.
- Affiliations
- Nagasaki University (JP)
- Nagasaki University Hospital (JP)
- Sasebo City General Hospital (JP)
- Mie University (JP)
- Venue
- Leukemia
- Published
- 2002-08-30
- Volume
- 16
- Issue
- 9
- Pages
- 1799-1807
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- OpenAlex
- W2332501724
- Cited by
- 45
- References
- 42
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 2 · 2021: 1 · 2020: 1 · 2019: 1 · 2017: 2 · 2016: 2 · 2015: 2 · 2014: 1 · 2012: 2
- FWCI
- 1.31
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Leukemia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Biochemical and Molecular Research
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- adult T-cell leukemia/lymphoma, MTAP, MTAP deficiency, 5'-deoxyadenosine, purine synthesis inhibitors, salvage pathway, methylthioadenosine, hematopoietic progenitor cells, targeted chemotherapy
- MeSH terms
- Adenosine Monophosphate, Antibiotics, Antineoplastic, Cell Division, Colony-Forming Units Assay, Humans, Lymphocyte Activation, Purine-Nucleoside Phosphorylase, RNA, Messenger, RNA, Neoplasm, Thymidine, Blotting, Southern, Leukemia-Lymphoma, Adult T-Cell, Gene Deletion, DNA Primers, Drug Resistance, Neoplasm, Reverse Transcriptase Polymerase Chain Reaction
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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