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Gene Review

MTAP  -  methylthioadenosine phosphorylase

Homo sapiens

Synonyms: 5'-methylthioadenosine phosphorylase, BDMF, DMSFH, DMSMFH, HEL-249, ...
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Disease relevance of MTAP


High impact information on MTAP


Chemical compound and disease context of MTAP


Biological context of MTAP

  • The gene (MTAP) encoding this enzyme was previously mapped to the short arm of chromosome 9, band p21-22, a region that is frequently deleted in multiple tumor types [8].
  • The location, expression pattern, and nucleotide sequence of this gene suggest that it codes for the MTAP enzyme [8].
  • The IFN gene cluster was homozygously deleted in 2 of 15 (13%) analyzed cases, whereas the MTAP gene was deleted in 6 of 15 cases (40%) [9].
  • MTAP(-) T-ALL-derived cell line, CEM cells were very sensitive to methionine deprivation, with cell viability at 50% of control as early as 48 hours after methionine deprivation [2].
  • Thus the MTAP loss in malignant cells may be an example of gene deletion chemoselectivity, in which genetic deletions that occur as part of the oncogenic process render these cells more sensitive to particular anticancer agents than normal cells, which have not undergone such deletions [10].

Anatomical context of MTAP


Associations of MTAP with chemical compounds

  • Alanosine, an inhibitor of AMP synthesis, inhibited the growth of both MTAP(+) (Molt-4 and Molt-16) and MTAP(-) (CEM and HSB2) cell lines [2].
  • Because MTAP phosphorolyzes 5'-deoxy-5'-methylthioadenosine (MTA), generated as a byproduct of polyamine synthesis, to the salvageable purine base adenine, loss of this pathway in p16(-), MTAP(-) cells might sensitize these cells to methotrexate (MTX), the mechanism of action of which involves, in part, an inhibition of purine de novo synthesis [10].
  • The function of MTAP is to salvage methylthioadenosine, which is produced as a byproduct of polyamine metabolism [3].
  • In contrast, MTAP(-) cell lines, which cannot recycle purines from endogenous MTA, have a relatively high sensitivity to the antipurine actions of MTX, which is not modulated by 5'-chloro-5'-deoxyformycin A or exogenous MTA [10].
  • MTAP expression causes a significant decrease in intracellular polyamine levels and alters the ratio of putrescine to total polyamines [3].

Enzymatic interactions of MTAP

  • Since the MTAP gene is often co-deleted with p16INK4A/CDKN2A, concurrent immunolabeling for both proteins can identify cases with homozygous p16INK4A/CDKN2A gene deletion [5].
  • Previously, we reported that the MTAP gene was deleted in over 30% of T-ALL patients at both diagnosis and relapse [14].

Regulatory relationships of MTAP

  • Furthermore, in MTAP re-expressing cells interferon (IFN)-alpha and IFN-gamma induced a significantly stronger inhibition of cell proliferation than in mock transfected cells [12].

Other interactions of MTAP

  • Quantitative PCR showed chromosome 9p deletions including p16 tumor suppressor gene (2 of 7 tumors) and MTAP gene (3 of 7) [15].
  • INTERPRETATION AND CONCLUSIONS: In this study of 227 cases of childhood B-lineage ALL, inactivation of CDKN2A, CDKN2B and MTAP did not influences the patients' outcome [16].
  • Quantitative polymerase chain reaction amplification of exon 8 of MTAP showed a deletion in 16 of 48 (33.3%) patients at diagnosis and in 13 of 33 (39.4%) patients at relapse [2].
  • A high frequency of deleted genes was observed in 6 of 11 cases (54.5%), including FGFR2, MTAP, and DMBT1 [17].
  • CONCLUSIONS: MTAP activity is frequently lost, and ODC activity is frequently elevated in both pancreatic adenocarcinoma and neuroendocrine tumors [18].

Analytical, diagnostic and therapeutic context of MTAP


  1. Genomic cloning of methylthioadenosine phosphorylase: a purine metabolic enzyme deficient in multiple different cancers. Nobori, T., Takabayashi, K., Tran, P., Orvis, L., Batova, A., Yu, A.L., Carson, D.A. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  2. Frequent deletion in the methylthioadenosine phosphorylase gene in T-cell acute lymphoblastic leukemia: strategies for enzyme-targeted therapy. Batova, A., Diccianni, M.B., Nobori, T., Vu, T., Yu, J., Bridgeman, L., Yu, A.L. Blood (1996) [Pubmed]
  3. Methylthioadenosine phosphorylase, a gene frequently codeleted with p16(cdkN2a/ARF), acts as a tumor suppressor in a breast cancer cell line. Christopher, S.A., Diegelman, P., Porter, C.W., Kruger, W.D. Cancer Res. (2002) [Pubmed]
  4. Lack of methylthioadenosine phosphorylase expression in mantle cell lymphoma is associated with shorter survival: implications for a potential targeted therapy. Marcé, S., Balagué, O., Colomo, L., Martinez, A., Höller, S., Villamor, N., Bosch, F., Ott, G., Rosenwald, A., Leoni, L., Esteller, M., Fraga, M.F., Montserrat, E., Colomer, D., Campo, E. Clin. Cancer Res. (2006) [Pubmed]
  5. Concordant loss of MTAP and p16/CDKN2A expression in gastroesophageal carcinogenesis: evidence of homozygous deletion in esophageal noninvasive precursor lesions and therapeutic implications. Powell, E.L., Leoni, L.M., Canto, M.I., Forastiere, A.A., Iocobuzio-Donahue, C.A., Wang, J.S., Maitra, A., Montgomery, E. Am. J. Surg. Pathol. (2005) [Pubmed]
  6. EFA (9-beta-D-erythrofuranosyladenine) is an effective salvage agent for methylthioadenosine phosphorylase-selective therapy of T-cell acute lymphoblastic leukemia with L-alanosine. Batova, A., Cottam, H., Yu, J., Diccianni, M.B., Carrera, C.J., Yu, A.L. Blood (2006) [Pubmed]
  7. Methylthioadenosine phosphorylase as target for chemoselective treatment of T-cell acute lymphoblastic leukemic cells. Efferth, T., Miyachi, H., Drexler, H.G., Gebhart, E. Blood Cells Mol. Dis. (2002) [Pubmed]
  8. Construction of a 2.8-megabase yeast artificial chromosome contig and cloning of the human methylthioadenosine phosphorylase gene from the tumor suppressor region on 9p21. Olopade, O.I., Pomykala, H.M., Hagos, F., Sveen, L.W., Espinosa, R., Dreyling, M.H., Gursky, S., Stadler, W.M., Le Beau, M.M., Bohlander, S.K. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  9. Refined mapping of genomic rearrangements involving the short arm of chromosome 9 in acute lymphoblastic leukemias and other hematologic malignancies. Dreyling, M.H., Bohlander, S.K., Le Beau, M.M., Olopade, O.I. Blood (1995) [Pubmed]
  10. Gene deletion chemoselectivity: codeletion of the genes for p16(INK4), methylthioadenosine phosphorylase, and the alpha- and beta-interferons in human pancreatic cell carcinoma lines and its implications for chemotherapy. Chen, Z.H., Zhang, H., Savarese, T.M. Cancer Res. (1996) [Pubmed]
  11. Homozygous deletion of the MTAP gene in invasive adenocarcinoma of the pancreas and in periampullary cancer: a potential new target for therapy. Hustinx, S.R., Hruban, R.H., Leoni, L.M., Iacobuzio-Donahue, C., Cameron, J.L., Yeo, C.J., Brown, P.N., Argani, P., Ashfaq, R., Fukushima, N., Goggins, M., Kern, S.E., Maitra, A. Cancer Biol. Ther. (2005) [Pubmed]
  12. Promoter-hypermethylation is causing functional relevant downregulation of methylthioadenosine phosphorylase (MTAP) expression in hepatocellular carcinoma. Hellerbrand, C., Mühlbauer, M., Wallner, S., Schuierer, M., Behrmann, I., Bataille, F., Weiss, T., Schölmerich, J., Bosserhoff, A.K. Carcinogenesis (2006) [Pubmed]
  13. Strong expression of methylthioadenosine phosphorylase (MTAP) in human colon carcinoma cells is regulated by TCF1/[beta]-catenin. Bataille, F., Rogler, G., Modes, K., Poser, I., Schuierer, M., Dietmaier, W., Ruemmele, P., Mühlbauer, M., Wallner, S., Hellerbrand, C., Bosserhoff, A.K. Lab. Invest. (2005) [Pubmed]
  14. Use of alanosine as a methylthioadenosine phosphorylase-selective therapy for T-cell acute lymphoblastic leukemia in vitro. Batova, A., Diccianni, M.B., Omura-Minamisawa, M., Yu, J., Carrera, C.J., Bridgeman, L.J., Kung, F.H., Pullen, J., Amylon, M.D., Yu, A.L. Cancer Res. (1999) [Pubmed]
  15. Molecular genetic alterations in radiation-induced astrocytomas. Brat, D.J., James, C.D., Jedlicka, A.E., Connolly, D.C., Chang, E., Castellani, R.J., Schmid, M., Schiller, M., Carson, D.A., Burger, P.C. Am. J. Pathol. (1999) [Pubmed]
  16. The prognostic significance of CDKN2A, CDKN2B and MTAP inactivation in B-lineage acute lymphoblastic leukemia of childhood. Results of the EORTC studies 58881 and 58951. Mirebeau, D., Acquaviva, C., Suciu, S., Bertin, R., Dastugue, N., Robert, A., Boutard, P., Méchinaud, F., Plouvier, E., Otten, J., Vilmer, E., Cavé, H. Haematologica (2006) [Pubmed]
  17. Detection of gene amplification and deletion in high-grade gliomas using a genome DNA microarray (GenoSensor Array 300). Sasaki, T., Arai, H., Beppu, T., Ogasawara, K. Brain tumor pathology. (2003) [Pubmed]
  18. Loss of methylthioadenosine phosphorylase and elevated ornithine decarboxylase is common in pancreatic cancer. Subhi, A.L., Tang, B., Balsara, B.R., Altomare, D.A., Testa, J.R., Cooper, H.S., Hoffman, J.P., Meropol, N.J., Kruger, W.D. Clin. Cancer Res. (2004) [Pubmed]
  19. A methylthioadenosine phosphorylase (MTAP) fusion transcript identifies a new gene on chromosome 9p21 that is frequently deleted in cancer. Schmid, M., Sen, M., Rosenbach, M.D., Carrera, C.J., Friedman, H., Carson, D.A. Oncogene (2000) [Pubmed]
  20. Methylthioadenosine phosphorylase regulates ornithine decarboxylase by production of downstream metabolites. Subhi, A.L., Diegelman, P., Porter, C.W., Tang, B., Lu, Z.J., Markham, G.D., Kruger, W.D. J. Biol. Chem. (2003) [Pubmed]
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