{"doi":"10.1002/ctm2.70015","title":"Low methylthioadenosine phosphorylase expression is associated with worse survival in patients with acute myeloid leukaemia","abstract":"Dear Editor, Deletions of methylthioadenosine phosphorylase (MTAP) are frequent in several malignancies and lead to 5′-deoxy-5′-methylthioadenosine (MTA) accumulation, competing with S-adenosylmethionine (SAM) for binding to Protein Arginine Methyltransferase 5 (PRMT5) and enhancing tumour sensitivity to PRMT5 inhibitors.1, 2 Although MTAP enzyme deficiency has been documented in acute myeloid leukaemia (AML), deletions of the MTAP gene have not been identified in this haematological malignancy. Here we evaluated MTAP downregulation in AML datasets (TCGA and OHSU)3-7 and its associations with clinical and molecular characteristics and patient's clinical outcome. When comparing the MTAP expression between AML bone marrow (BM) (n = 542) and healthy BM (n = 73), different MTAP probes showed different results (MILE dataset,8 Figure 1A–F). However, when comparing the GTEx and TCGA datasets on UCSC Xena,9 we found higher MTAP expression in AML blood (n = 173) than normal blood samples (n = 337) (median-log2: 4.040 vs. −0.199, p = 6.596e−197, Figure 1G). Thirteen transcripts of MTAP were differentially expressed (Figure 1H). While only one deep deletion case was identified in AML in the TCGA dataset, using Z-score < −1 to define low expressor MTAP, we found 10.40% and 16.84% of cases have low MTAP expression in the TCGA and OHSU, respectively (Figure 1I). To investigate whether low expression of MTAP is associated with specific baseline clinical features in patients with AML, we compared the frequency of MTAP low expression according to diagnosis age, sex, BM blast percentage, white blood cell count, peripheral blasts percentage, cytogenetic risk and molecular risk (Tables S1 and S2). In the TCGA dataset, we found MTAP low expression to be more frequent in older patients (diagnosis age ≥ 65 years) than in younger patients (diagnosis age < 65 years) (18.87% vs. 6.67%, p = .027). MTAP expression levels were found to be lower in patients with AML M3 (n = 16) than AML M2 (n = 38) (p = .030, Figure 2A). We also assessed the association between MTAP low expression and AML molecular characteristics in terms of the presence of certain AML mutations (Tables S3 and S4). We compared the frequencies of FLT3, DNMT3A, NPM1, IDH2, IDH1 and TP53 mutations between low and unaltered/high MTAP patients. In OHSU, patients with MTAP low expression have a lower frequency of FLT3 mutations (17.3% vs. 32.1%, p = .036) and NPM1 mutation (3.8% vs. 30.6%, p < .001) compared with unaltered/high MTAP group. MTAP was expressed at significantly higher levels in patients with NPM1 mutation (median-log2, TCGA: 1037 vs. 857.5, p = .0018, adjusted-p = .0112; OHSU: 4.058 vs. 3.606, p < .001, adjusted-p < .001), DNMT3A mutation (median-log2, TCGA: 980.3 vs. 844.0, p = .0094, adjusted-p = .0569; OHSU: 3.887 vs. 3.702, p = .048, adjusted-p = .288), FLT3 mutation (median-log2, OHSU: 3.905 vs. 3.670, p = .007, adjusted-p = .044), compared with patients carrying wild type genes (Figure 2B–F). Survival analyses showed that the overall survival (OS) of MTAP-low patients was significantly shorter than that of unaltered/high MTAP patients (MTAP-low patients vs. MTAP- unaltered/high patients; median-OS [months]: TCGA: 7.5 vs. 20.5, p = .014; OHSU: 10.16 vs. 17.79, p = .02, Figure 3A,B). Additionally, the disease-free survival (DFS) of MTAP-low patients was significantly lower than MTAP-unaltered/high patients in the TCGA dataset (MTAP-low patients (n = 18) vs. MTAP-unaltered/high patients (n = 153); median-DFS (months): 8.200 vs. 17.00, p = .017, Figure 3C). The OHSU dataset does not contain DFS data. We also conducted survival analyses after the exclusion of patients with AML M3, and patients with no available FAB data, due to the favourable prognosis of all-trans retinoic acid therapy. MTAP-low patients still have worse outcomes compared with MTAP-unaltered/high patients (TCGA: MTAP-low patients (n = 16) vs. MTAP-unaltered/high patients (n = 139); median OS (months): 7.200 vs. ","journal":"Clinical and Translational Medicine","year":2024,"id":503150,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9577,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1352766,"name":"Qianqian Peng","orcid":"0009-0002-8459-6026","position":1,"is_corresponding":false},{"id":1320382,"name":"Advaith Maya Sanjeev Kumar","orcid":null,"position":2,"is_corresponding":false},{"id":497048,"name":"Houda Alachkar","orcid":"0000-0001-5567-5521","position":3,"is_corresponding":false},{"id":1352765,"name":"Yiyu Xiao","orcid":"0009-0004-0666-0365","position":0,"is_corresponding":true}],"reference_count":5,"raw_metadata":null,"created_at":"2026-07-19T02:10:27.781502Z","pmid":"39259513","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}