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Lack of expression of MTAP in uncommon T-cell lymphomas
Joseph R Bertino1, Martin Lubin, Nadine Johnson-Farley
1Department of Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 18901, USA. bertinoj@umdnj.edu
Unlabelled:
The majority of peripheral T-cell lymphomas were found to lack methylthioadenosine phosphorylase, an enzyme that is essential for the salvage of adenine from methylthioadenosine, a product of polyamine synthesis. Importantly, tumors that lack this enzyme have been shown to be more sensitive to inhibitors of de novo purine synthesis (6-thioguanine, methotrexate).
Background:
T-cell lymphomas, in particular peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL), and anaplastic large cell lymphoma (ALCL), have only limited and noncurative treatment options.
Patients And Methods:
We report here that a high percentage of PTCL, AITL, and ALCL lack the enzyme methylthioadenosine phosphorylase (MTAP), as do T-cell leukemia and T-cell lymphoblastic leukemia. MTAP-deficient cells cannot cleave endogenous methylthioadenosine to adenine and 5-methylthioribose-1-phosphate, a precursor of methionine, and as a result have enhanced sensitivity to inhibitors of de novo purine biosynthesis. A recently introduced antifolate, pralatrexate, which has been shown to inhibit de novo purine biosynthesis, has been approved for treatment of PTCL and may have an increasing role in therapy. An alternative strategy involving coadministration of methylthioadenosine and high-dose 6-thioguanine has been proposed and may prove to be selectively toxic to MTAP-deficient uncommon lymphomas.
Conclusion:
Thus the consequences of MTAP deficiency suggest that new therapeutic interventions for T-cell lymphoma may be feasible.
Insights
Peripheral T-cell lymphomas often lack methylthioadenosine phosphorylase (MTAP). This deficiency makes tumors more sensitive to purine synthesis inhibitors, suggesting new therapeutic strategies for these uncommon lymphomas.
Area of Science:
- Oncology
- Biochemistry
- Cancer Metabolism
Background:
- Peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma (AITL) and anaplastic large cell lymphoma (ALCL), have limited treatment options.
- These lymphomas are aggressive and often associated with poor prognoses.
Purpose of the Study:
- To investigate the role of methylthioadenosine phosphorylase (MTAP) deficiency in T-cell lymphomas.
- To explore potential therapeutic strategies targeting MTAP-deficient lymphomas.
Main Methods:
- Assessed MTAP enzyme levels in various T-cell lymphomas, including PTCL, AITL, and ALCL.
- Analyzed the sensitivity of MTAP-deficient cells to inhibitors of de novo purine biosynthesis.
Main Results:
- A high percentage of PTCL, AITL, and ALCL were found to be deficient in MTAP.
- MTAP-deficient cells exhibit enhanced sensitivity to inhibitors of de novo purine biosynthesis, such as 6-thioguanine and methotrexate.
- The antifolate pralatrexate, an inhibitor of de novo purine biosynthesis, is approved for PTCL treatment and may be effective in MTAP-deficient cases.
Conclusions:
- MTAP deficiency is a common feature in T-cell lymphomas.
- Targeting purine biosynthesis pathways presents a promising therapeutic avenue for MTAP-deficient T-cell lymphomas.
- Further research into MTAP deficiency could lead to novel treatment strategies for these challenging cancers.
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