title: Lack of expression of MTAP in uncommon T-cell lymphomas.
abstract: 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.
  
  
  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.
  
  
  CONCLUSIONS
  Thus the consequences of MTAP deficiency suggest that new therapeutic interventions for T-cell lymphoma may be feasible.
authors.affiliation: Department of Medicine, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, New Brunswick, NJ 18901, USA. bertinoj@umdnj.edu
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Bertino
authors.forename: Martin
authors.initials: M
authors.lastname: Lubin
authors.forename: Nadine
authors.initials: N
authors.lastname: Johnson-Farley
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.forename: Lauri
authors.initials: L
authors.lastname: Goodell
authors.forename: Sharathkumar
authors.initials: S
authors.lastname: Bhagavathi
mesh_terms: D000225:Adenine / Q000378:metabolism; D000630:Aminopterin / Q000031:analogs & derivatives / Q000627:therapeutic use; D005493:Folic Acid Antagonists / Q000627:therapeutic use; D006801:Humans; D016399:Lymphoma, T-Cell / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism; D011683:Purine-Nucleoside Phosphorylase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D011687:Purines / Q000096:biosynthesis / Q000378:metabolism; D013866:Thioguanine / Q000378:metabolism; D046888:Tissue Array Analysis
chemical_list: C418863:10-propargyl-10-deazaaminopterin; D005493:Folic Acid Antagonists; D011687:Purines; D011683:Purine-Nucleoside Phosphorylase; C021784:5'-methylthioadenosine phosphorylase; D013866:Thioguanine; D000225:Adenine; D000630:Aminopterin; C030985:purine