{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T23:06:33Z","timestamp":1778540793177,"version":"3.51.4"},"reference-count":34,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T00:00:00Z","timestamp":1723075200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fondo de Investigaciones Sanitarias\/Instituto de Salud Carlos III (ISCIII)","award":["PI19\/01476"],"award-info":[{"award-number":["PI19\/01476"]}]},{"name":"Fondo de Investigaciones Sanitarias\/Instituto de Salud Carlos III (ISCIII)","award":["PI22\/01660"],"award-info":[{"award-number":["PI22\/01660"]}]},{"name":"European Union","award":["PI19\/01476"],"award-info":[{"award-number":["PI19\/01476"]}]},{"name":"European Union","award":["PI22\/01660"],"award-info":[{"award-number":["PI22\/01660"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Two new diagnostic classifications of acute myeloid leukemia (AML) were published in 2022 to update current knowledge on disease biology. In previous 2017-edition categories of AML with myelodysplasia-related changes, AML was not otherwise specified, but AML with mutated RUNX1 experienced profound changes. We performed whole exome sequencing on a cohort of 69 patients with cytogenetic intermediate-risk AML that belonged to these diagnostic categories to correlate their mutational pattern and copy-number alterations with their new diagnostic distribution. Our results show that 45% of patients changed their diagnostic category, being AML myelodysplasia-related the most enlarged, mainly due to a high frequency of myelodysplasia-related mutations (58% of patients). These showed a good correlation with multilineage dysplasia and\/or myelodysplastic syndrome history, but at the same time, 21% of de novo patients without dysplasia also presented them. RUNX1 was the most frequently mutated gene, with a high co-occurrence rate with other myelodysplasia-related mutations. We found a high prevalence of copy-neutral loss of heterozygosity, frequently inducing a homozygous state in particular mutated genes. Mild differences in current classifications explain the diagnostic disparity in 10% of patients, claiming a forthcoming unified classification.<\/jats:p>","DOI":"10.3390\/ijms25168669","type":"journal-article","created":{"date-parts":[[2024,8,8]],"date-time":"2024-08-08T15:04:24Z","timestamp":1723129464000},"page":"8669","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Whole Exome Sequencing of Intermediate-Risk Acute Myeloid Leukemia without Recurrent Genetic Abnormalities Offers Deeper Insights into New Diagnostic Classifications"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6376-0929","authenticated-orcid":false,"given":"Francesca","family":"Guijarro","sequence":"first","affiliation":[{"name":"Hematopathology Section, Pathology Department, Hospital Cl\u00ednic Barcelona, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9044-4665","authenticated-orcid":false,"given":"Sandra","family":"Casta\u00f1o-D\u00edez","sequence":"additional","affiliation":[{"name":"Hematopathology Section, Pathology Department, Hospital Cl\u00ednic Barcelona, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9548-4305","authenticated-orcid":false,"given":"Carlos","family":"Jim\u00e9nez-Vicente","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Hematology Department, Hospital Cl\u00ednic Barcelona, 08036 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8571-1466","authenticated-orcid":false,"given":"Marta","family":"Garrote","sequence":"additional","affiliation":[{"name":"Hematopathology Section, Pathology Department, Hospital Cl\u00ednic Barcelona, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8579-082X","authenticated-orcid":false,"given":"Jos\u00e9 Ram\u00f3n","family":"\u00c1lamo","sequence":"additional","affiliation":[{"name":"Hematopathology Section, Pathology Department, Hospital Cl\u00ednic Barcelona, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"G\u00f3mez-Hernando","sequence":"additional","affiliation":[{"name":"Hematopathology Section, Pathology Department, Hospital Cl\u00ednic Barcelona, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Irene","family":"L\u00f3pez-Oreja","sequence":"additional","affiliation":[{"name":"Hematopathology Section, Pathology Department, Hospital Cl\u00ednic Barcelona, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordi","family":"Morata","sequence":"additional","affiliation":[{"name":"Centro Nacional de An\u00e1lisis Gen\u00f3mico (CNAG), 08028 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5545-0178","authenticated-orcid":false,"given":"M\u00f2nica","family":"L\u00f3pez-Guerra","sequence":"additional","affiliation":[{"name":"Hematopathology Section, Pathology Department, Hospital Cl\u00ednic Barcelona, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Biomedical Research Networking Center on Oncology (CIBERONC), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6644-1659","authenticated-orcid":false,"given":"Cristina","family":"L\u00f3pez","sequence":"additional","affiliation":[{"name":"Hematopathology Section, Pathology Department, Hospital Cl\u00ednic Barcelona, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Biomedical Research Networking Center on Oncology (CIBERONC), 28029 Madrid, Spain"},{"name":"Facultat de Medicina, Universitat de Barcelona, 08007 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S\u00edlvia","family":"Be\u00e0","sequence":"additional","affiliation":[{"name":"Hematopathology Section, Pathology Department, Hospital Cl\u00ednic Barcelona, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Biomedical Research Networking Center on Oncology (CIBERONC), 28029 Madrid, Spain"},{"name":"Facultat de Medicina, Universitat de Barcelona, 08007 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dolors","family":"Costa","sequence":"additional","affiliation":[{"name":"Hematopathology Section, Pathology Department, Hospital Cl\u00ednic Barcelona, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Biomedical Research Networking Center on Oncology (CIBERONC), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7486-8484","authenticated-orcid":false,"given":"Dolors","family":"Colomer","sequence":"additional","affiliation":[{"name":"Hematopathology Section, Pathology Department, Hospital Cl\u00ednic Barcelona, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Biomedical Research Networking Center on Oncology (CIBERONC), 28029 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marina","family":"D\u00edaz-Bey\u00e1","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Hematology Department, Hospital Cl\u00ednic Barcelona, 08036 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Rozman","sequence":"additional","affiliation":[{"name":"Hematopathology Section, Pathology Department, Hospital Cl\u00ednic Barcelona, 08036 Barcelona, Spain"},{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jordi","family":"Esteve","sequence":"additional","affiliation":[{"name":"Institut d\u2019Investigacions Biom\u00e8diques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain"},{"name":"Hematology Department, Hospital Cl\u00ednic Barcelona, 08036 Barcelona, Spain"},{"name":"Facultat de Medicina, Universitat de Barcelona, 08007 Barcelona, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1038\/s41375-022-01613-1","article-title":"The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic\/Dendritic Neoplasms","volume":"36","author":"Khoury","year":"2022","journal-title":"Leukemia"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1182\/blood.2022015850","article-title":"International Consensus Classification of Myeloid Neoplasms and Acute Leukemia: Integrating Morphological, Clinical, and Genomic Data","volume":"140","author":"Arber","year":"2022","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.1182\/blood-2014-11-610543","article-title":"Acute myeloid leukemia ontogeny is de-fined by distinct somatic mutations","volume":"125","author":"Lindsley","year":"2015","journal-title":"Blood"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1182\/blood-2016-01-693879","article-title":"Spectrum and prognostic relevance of driver gene mutations in acute myeloid leukemia","volume":"128","author":"Metzeler","year":"2016","journal-title":"Blood"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4622","DOI":"10.1038\/s41467-022-32103-8","article-title":"Unified classification and risk-stratification in Acute Myeloid Leukemia","volume":"13","author":"Tazi","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5000","DOI":"10.1182\/bloodadvances.2023009675","article-title":"Interaction between myelodysplasia-related gene mutations and ontogeny in acute myeloid leukemia","volume":"7","author":"McCarter","year":"2023","journal-title":"Blood Adv."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1038\/s41408-022-00774-7","article-title":"Poor prognostic implications of myelodysplasia-related mutations in both older and younger patients with de novo AML","volume":"13","author":"Tsai","year":"2023","journal-title":"Blood Cancer J."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1182\/blood.2022016867","article-title":"Diagnosis and Management of AML in Adults: 2022 ELN Recommendations from an International Expert Panel","volume":"140","author":"Wei","year":"2022","journal-title":"Blood"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1038\/s41375-023-01884-2","article-title":"Validation and refinement of the 2022 European LeukemiaNet genetic risk stratification of acute myeloid leukemia","volume":"37","author":"Rausch","year":"2023","journal-title":"Leukemia"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"256","DOI":"10.1111\/bjh.19518","article-title":"Evaluation of European LeukemiaNet 2022 risk classification in patients undergoing allogeneic haematopoietic stem cell transplanta-tion for acute myeloid leukaemia: Identification of a very poor prognosis genetic group","volume":"205","author":"Charry","year":"2024","journal-title":"Br. J. Haematol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"5799","DOI":"10.1182\/bloodadvances.2023009742","article-title":"Germ line variants in patients with acute myeloid leukemia without a suspicion of hereditary hematologic malignancy syndrome","volume":"7","author":"Guijarro","year":"2023","journal-title":"Blood Adv."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"424","DOI":"10.1182\/blood-2016-08-733196","article-title":"Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel","volume":"129","author":"Estey","year":"2017","journal-title":"Blood"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1413","DOI":"10.1038\/s41375-023-01909-w","article-title":"AML classification in the year 2023: How to avoid a Babylonian confusion of languages","volume":"37","author":"Huber","year":"2023","journal-title":"Leukemia"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"5122","DOI":"10.1182\/bloodadvances.2023010173","article-title":"Applicability of 2022 classifications of acute myeloid leukemia in the real-world setting","volume":"7","author":"Attardi","year":"2023","journal-title":"Blood Adv."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1939","DOI":"10.1038\/s41375-022-01631-z","article-title":"AML, NOS and AML-MRC as defined by multi-lineage dysplasia share a common mutation pattern which is distinct from AML-MRC as defined by MDS-related cytogenetics","volume":"36","author":"Fuhrmann","year":"2022","journal-title":"Leukemia"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1182\/blood.2019000942","article-title":"Genetics of progression from MDS to secondary leukemia","volume":"136","author":"Menssen","year":"2020","journal-title":"Blood"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"626","DOI":"10.3324\/haematol.2017.181842","article-title":"Association of mutations with morphological dysplasia in de novo acute myeloid leukemia without 2016 WHO Classification-defined cytogenetic abnormalities","volume":"103","author":"Weinberg","year":"2018","journal-title":"Haematologica"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2160","DOI":"10.1038\/leu.2016.126","article-title":"RUNX1 mutations in acute myeloid leu-kemia are associated with distinct clinico-pathologic and genetic features","volume":"30","author":"Gaidzik","year":"2016","journal-title":"Leukemia"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1395","DOI":"10.1080\/10428194.2020.1723016","article-title":"Comparison of mutational profiles and clinical out-comes in patients with acute myeloid leukemia with mutated RUNX1 versus acute myeloid leukemia with myelodysplasia-related changes with mutated RUNX1","volume":"61","author":"Nguyen","year":"2020","journal-title":"Leuk. Lymphoma"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"218","DOI":"10.1016\/j.cancergen.2018.07.005","article-title":"Assessing copy number abnormalities and copy-neutral loss-of-heterozygosity across the genome as best practice in diagnostic evaluation of acute myeloid leukemia: An evidence-based review from the cancer genomics consortium (CGC) myeloid neoplasms working group","volume":"228\u2013229","author":"Xu","year":"2018","journal-title":"Cancer Genet."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2900","DOI":"10.1002\/cncr.29475","article-title":"Prognostic significance of acquired copy-neutral loss of heterozygosity in acute myeloid leukemia","volume":"121","author":"Gronseth","year":"2015","journal-title":"Cancer"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6524","DOI":"10.1158\/1078-0432.CCR-19-0725","article-title":"Genetic Characterization and Prognostic Relevance of Acquired Uniparental Disomies in Cytogenetically Normal Acute Myeloid Leukemia","volume":"25","author":"Walker","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1038\/leu.2009.263","article-title":"Identification of acquired copy number alterations and uniparental disomies in cytogenetically normal acute myeloid leukemia using high-resolution single-nucleotide polymorphism analysis","volume":"24","author":"Bullinger","year":"2010","journal-title":"Leukemia"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"9152","DOI":"10.1158\/0008-5472.CAN-05-2017","article-title":"Association between acquired uniparental disomy and homozygous gene mutation in acute myeloid leukemias","volume":"65","author":"Fitzgibbon","year":"2005","journal-title":"Cancer Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2209","DOI":"10.1056\/NEJMoa1516192","article-title":"Genomic Classification and Prognosis in Acute Myeloid Leukemia","volume":"374","author":"Papaemmanuil","year":"2016","journal-title":"N. Engl. J. Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1182\/blood-2009-11-254441","article-title":"Refinement of cytogenetic classification in acute myeloid leukemia: Determination of prognostic significance of rare recurring chromosomal abnormalities among 5876 younger adult patients treated in the United Kingdom Medical Research Council trials","volume":"116","author":"Grimwade","year":"2010","journal-title":"Blood"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1038\/s41586-018-0623-z","article-title":"Functional genomic landscape of acute mye-loid leukaemia","volume":"562","author":"Tyner","year":"2018","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"900","DOI":"10.1182\/bloodadvances.2020003709","article-title":"Genomic characterization of relapsed acute myeloid leukemia reveals novel putative therapeutic targets","volume":"5","author":"Stratmann","year":"2021","journal-title":"Blood Adv."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1016\/j.ccell.2015.03.017","article-title":"Inherited and Somatic Defects in DDX41 in Myeloid Neoplasms","volume":"27","author":"Polprasert","year":"2015","journal-title":"Cancer Cell"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"D886","DOI":"10.1093\/nar\/gky1016","article-title":"CADD: Predicting the deleteriousness of variants throughout the human genome","volume":"47","author":"Rentzsch","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"986","DOI":"10.1016\/j.gim.2022.01.001","article-title":"Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC)","volume":"24","author":"Horak","year":"2022","journal-title":"Genet. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"16910","DOI":"10.1073\/pnas.1009843107","article-title":"Allele-specific copy number analysis of tumors","volume":"107","author":"Nordgard","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Hanssen, F., Garcia, M.U., Folkersen, L., Pedersen, A.S., Lescai, F., Jodoin, S., Miller, E., Seybold, M., Wacker, O., and Smith, N. (2024). Scalable and efficient DNA sequencing analysis on different compute infrastructures aiding variant discovery. NAR Genom. Bioinform., 6.","DOI":"10.1093\/nargab\/lqae031"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1101\/gr.239244.118","article-title":"Maftools: Efficient and comprehensive analysis of somatic variants in cancer","volume":"28","author":"Mayakonda","year":"2018","journal-title":"Genome Res."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/16\/8669\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T15:32:17Z","timestamp":1760110337000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/16\/8669"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,8,8]]},"references-count":34,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2024,8]]}},"alternative-id":["ijms25168669"],"URL":"https:\/\/doi.org\/10.3390\/ijms25168669","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,8,8]]}}}