{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T22:03:43Z","timestamp":1783461823549,"version":"3.55.0"},"reference-count":41,"publisher":"American Society of Hematology","issue":"1","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2025,12,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>In the past 20 years, advances in genomic technologies have greatly improved our understanding of pediatric acute myeloid leukemia (AML). Today, cytogenetic tests can detect structural changes in approximately 75% of cases and remain a main tool for assessing risk. Recent technologies, such as next-generation sequencing, are revealing additional structural alterations (cryptic fusions) and mutations that often cooperate to influence disease biology and treatment response. This evolving genetic landscape has identified unique childhood subtypes of AML defined by specific fusions, such as NUP98::NSD1, CBFA2T3::GLIS2, and varied KMT2A rearrangements, which are linked to distinct clinical outcomes. Emerging data also point to the poor prognosis associated with certain subtypes of NPM1, like the NPM1-D isoform. Additionally, mutations in genes like WT1, DNMT3A, and TP53, the latter of which are rare in childhood AML, may influence patients' outcomes, particularly when occurring in combination. Targeted therapies, including FLT3, BCL2, and menin inhibitors, are beginning to reshape treatment, offering more personalized approaches. However, integrating these drugs effectively into the patient's treatment strategy remains challenging due to the genetic complexity and rarity of pediatric AML. Key issues ahead include identifying which genetic features truly affect outcomes, using this information to personalize therapy, predicting who will benefit from targeted drugs, and choosing the best markers to track disease response over time. Looking forward, collaborative efforts are urgently needed to validate pediatric-specific biomarkers, test novel drug combinations, and link genetic data to clinical outcomes to design trials and future treatment strategies.<\/jats:p>","DOI":"10.1182\/hematology.2025000714","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T14:08:18Z","timestamp":1764943698000},"page":"270-278","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":1,"title":["Using genomics to refine pediatric AML risk stratification"],"prefix":"10.1182","volume":"2025","author":[{"given":"Martina","family":"Pigazzi","sequence":"first","affiliation":[{"name":"1 Department of Women's and Children's Health, Onco-hematology Lab and Clinic, University of Padova, Padova, Italy"},{"name":"2 Foundation Istituto Ricerca Pediatrica (IRP), Padova, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soheil","family":"Meshinchi","sequence":"additional","affiliation":[{"name":"3 Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Franco","family":"Locatelli","sequence":"additional","affiliation":[{"name":"4 Department of Pediatric Hematology and Oncology, IRCCS Ospedale Pediatrico Bambino Ges\u00f9, Rome, Italy"},{"name":"5 Catholic University of the Sacred Heart, Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"234","published-online":{"date-parts":[[2025,12,5]]},"reference":[{"issue":"1","key":"2025120616330519100_hem2025000714C1","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nm.4439","article-title":"The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions","volume":"24","author":"Bolouri","year":"2018","journal-title":"Nat Med"},{"issue":"2","key":"2025120616330519100_hem2025000714C2","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1038\/s41588-023-01640-3","article-title":"A new genomic framework to categorize pediatric acute myeloid leukemia","volume":"56","author":"Umeda","year":"2024","journal-title":"Nat Genet"},{"issue":"1","key":"2025120616330519100_hem2025000714C3","doi-asserted-by":"crossref","first-page":"48","DOI":"10.3324\/haematol.2021.280250","article-title":"Analysis of rare driving events in pediatric acute myeloid leukemia","volume":"108","author":"Noort","year":"2023","journal-title":"Haematologica"},{"issue":"7","key":"2025120616330519100_hem2025000714C4","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"},{"issue":"3","key":"2025120616330519100_hem2025000714C5","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1038\/leu.2010.316","article-title":"MLL partner genes drive distinct gene expression profiles and genomic alterations in pediatric acute myeloid leukemia: an AIEOP study","volume":"25","author":"Pigazzi","year":"2011","journal-title":"Leukemia"},{"issue":"16","key":"2025120616330519100_hem2025000714C6","doi-asserted-by":"crossref","first-page":"2963","DOI":"10.1200\/JCO.22.02120","article-title":"Measurable residual disease and fusion partner independently predict survival and relapse risk in childhood KMT2A-rearranged acute myeloid leukemia: a study by the international Berlin-Frankfurt-M\u00fcnster study group","volume":"41","author":"van Weelderen","year":"2023","journal-title":"J Clin Oncol"},{"issue":"3","key":"2025120616330519100_hem2025000714C7","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1038\/ng.2894","article-title":"Identification of functional cooperative mutations of SETD2 in human acute leukemia","volume":"46","author":"Zhu","year":"2014","journal-title":"Nat Genet"},{"key":"2025120616330519100_hem2025000714C8","doi-asserted-by":"crossref","first-page":"609","DOI":"10.1182\/blood-2021-147565","article-title":"KMT2A partial tandem duplications (KMT2A-PTD) is a rare, but recurrent genomic event in childhood AML and associated with high rate of co-occurring FLT3 mutations","volume":"138","author":"Kirkey","year":"2021","journal-title":"Blood"},{"issue":"5","key":"2025120616330519100_hem2025000714C9","doi-asserted-by":"crossref","first-page":"1132","DOI":"10.1038\/leu.2013.339","article-title":"Core-binding factor acute myeloid leukemia in pediatric patients enrolled in the AIEOP AML 2002\/01 trial: screening and prognostic impact of c-KIT mutations","volume":"28","author":"Manara","year":"2014","journal-title":"Leukemia"},{"key":"2025120616330519100_hem2025000714C10","doi-asserted-by":"crossref","first-page":"20406207251330064","DOI":"10.1177\/20406207251330064","article-title":"Molecular genetics profiling of core-binding factor acute myeloid leukemia in pediatrics","volume":"16","author":"Hu","year":"2025","journal-title":"Ther Adv Hematol"},{"issue":"20","key":"2025120616330519100_hem2025000714C11","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1182\/blood-2015-12-688705","article-title":"Comprehensive mutational profiling of core binding factor acute myeloid leukemia","volume":"127","author":"Duployez","year":"2016","journal-title":"Blood"},{"issue":"23","key":"2025120616330519100_hem2025000714C12","doi-asserted-by":"crossref","first-page":"2587","DOI":"10.1182\/blood.V126.23.2587.2587","article-title":"ASXL1 and ASXL2 mutations in childhood AML are strongly associated with t(8;21) but do not independently impact on prognosis: a report from the Children's Oncology Group and NCI\/COG target initiative","volume":"126","author":"Farrar","year":"2015","journal-title":"Blood"},{"issue":"3","key":"2025120616330519100_hem2025000714C13","doi-asserted-by":"crossref","first-page":"e99","DOI":"10.3324\/haematol.2014.114579","article-title":"Minimal residual disease monitored after induction therapy by RQ-PCR can contribute to tailor treatment of patients with t(8;21) runx1-runx1t1 rearrangement","volume":"100","author":"Pigazzi","year":"2015","journal-title":"Haematologica"},{"issue":"4","key":"2025120616330519100_hem2025000714C14","doi-asserted-by":"crossref","first-page":"974","DOI":"10.1038\/leu.2016.361","article-title":"NUP98-fusion transcripts characterize different biological entities within acute myeloid leukemia: a report from the AIEOP-AML group","volume":"31","author":"Bisio","year":"2017","journal-title":"Leukemia"},{"issue":"8","key":"2025120616330519100_hem2025000714C15","doi-asserted-by":"crossref","first-page":"2044","DOI":"10.3324\/haematol.2022.281653","article-title":"Comprehensive molecular and clinical characterization of NUP98 fusions in pediatric acute myeloid leukemia","volume":"108","author":"Bertrums","year":"2023","journal-title":"Haematologica"},{"key":"2025120616330519100_hem2025000714C16","doi-asserted-by":"publisher","DOI":"10.1101\/2025.01.21.25320683","article-title":"Fusion oncoproteins and cooperating mutations define disease phenotypes in NUP98- rearranged leukemia","author":"Umeda","year":"2025","journal-title":"medRxiv"},{"issue":"1","key":"2025120616330519100_hem2025000714C17","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1186\/s40001-024-02042-9","article-title":"Targeted gene sequencing and transcriptome sequencing reveal characteristics of NUP98 rearrangement in pediatric acute myeloid leukemia","volume":"29","author":"Zhang","year":"2024","journal-title":"Eur J Med Res"},{"issue":"17","key":"2025120616330519100_hem2025000714C18","doi-asserted-by":"crossref","first-page":"3469","DOI":"10.1182\/blood-2012-11-469825","article-title":"CBFA2T3-GLIS2 fusion transcript is a novel common feature in pediatric, cytogenetically normal AML, not restricted to FAB M7 subtype","volume":"121","author":"Masetti","year":"2013","journal-title":"Blood"},{"issue":"5","key":"2025120616330519100_hem2025000714C19","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.ccr.2012.10.007","article-title":"An Inv(16)(p13.3q24.3)- encoded CBFA2T3-GLIS2 fusion protein defines an aggressive subtype of pediatric acute megakaryoblastic leukemia","volume":"22","author":"Gruber","year":"2012","journal-title":"Cancer Cell"},{"issue":"22","key":"2025120616330519100_hem2025000714C20","doi-asserted-by":"crossref","first-page":"e157101","DOI":"10.1172\/JCI157101","article-title":"CBFA2T3-GLIS2 model of pediatric acute megakaryoblastic leukemia identifies FOLR1 as a CAR T cell target","volume":"132","author":"Le","year":"2022","journal-title":"J Clin Invest"},{"issue":"4","key":"2025120616330519100_hem2025000714C21","doi-asserted-by":"crossref","first-page":"777","DOI":"10.3390\/cancers13040777","article-title":"Infant acute myeloid leukemia: a unique clinical and biological entity","volume":"13","author":"Calvo","year":"2021","journal-title":"Cancers"},{"issue":"1","key":"2025120616330519100_hem2025000714C22","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1038\/leu.2016.177","article-title":"Characterization of children with FLT3-ITD acute myeloid leukemia: a report from the AIEOP AML-2002 study group","volume":"31","author":"Manara","year":"2017","journal-title":"Leukemia"},{"issue":"12","key":"2025120616330519100_hem2025000714C23","doi-asserted-by":"crossref","first-page":"3654","DOI":"10.1182\/blood-2006-03-009233","article-title":"Clinical implications of FLT3 mutations in pediatric AML","volume":"108","author":"Meshinchi","year":"2006","journal-title":"Blood"},{"issue":"12","key":"2025120616330519100_hem2025000714C24","doi-asserted-by":"crossref","first-page":"4326","DOI":"10.1182\/blood.V99.12.4326","article-title":"Analysis of FLT3-activating mutations in 979 patients with acute myelogenous leukemia: association with FAB subtypes and identification of subgroups with poor prognosis","volume":"99","author":"Thiede","year":"2002","journal-title":"Blood"},{"issue":"1","key":"2025120616330519100_hem2025000714C25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41408-019-0268-7","article-title":"Nucleophosmin mutations confer an independent favorable prognostic impact in 869 pediatric patients with acute myeloid leukemia","volume":"10","author":"Xu","year":"2020","journal-title":"Blood Cancer J"},{"issue":"9","key":"2025120616330519100_hem2025000714C26","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1182\/bloodadvances.2023011980","article-title":"Prognostic impact of cooccurring mutations in FLT3-ITD pediatric acute myeloid leukemia","volume":"8","author":"Tarlock","year":"2024","journal-title":"Blood Adv"},{"issue":"1","key":"2025120616330519100_hem2025000714C27","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1182\/blood-2004-02-0660","article-title":"Identification of a novel activating mutation (Y842C) within the activation loop of FLT3 in patients with acute myeloid leukemia (AML)","volume":"105","author":"Kindler","year":"2005","journal-title":"Blood"},{"issue":"6","key":"2025120616330519100_hem2025000714C28","doi-asserted-by":"crossref","first-page":"1855","DOI":"10.1182\/blood-2004-02-0712","article-title":"Identifying and characterizing a novel activating mutation of the FLT3 tyrosine kinase in AML","volume":"104","author":"Jiang","year":"2004","journal-title":"Blood"},{"key":"2025120616330519100_hem2025000714C29","doi-asserted-by":"crossref","first-page":"463","DOI":"10.3389\/fped.2019.00463","article-title":"Targeted therapies for pediatric AML: gaps and perspective","volume":"7","author":"Lonetti","year":"2019","journal-title":"Front Pediatr"},{"issue":"8","key":"2025120616330519100_hem2025000714C30","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1200\/JCO-24-01715","article-title":"Influence of nucleophosmin (NPM1) genotypes on outcome of patients with AML: an AIEOP-BFM and COG-SWOG intergroup collaboration","volume":"43","author":"Tregnago","year":"2025","journal-title":"J Clin Oncol"},{"issue":"1","key":"2025120616330519100_hem2025000714C31","doi-asserted-by":"crossref","first-page":"4306","DOI":"10.1182\/blood-2023-181060","article-title":"DNMT3A mutants are enriched in NPMc+ AML and associated with adverse outcome in childhood AML","volume":"142","author":"Ries","year":"2023","journal-title":"Blood"},{"issue":"19","key":"2025120616330519100_hem2025000714C32","doi-asserted-by":"crossref","first-page":"5941","DOI":"10.1182\/bloodadvances.2022008282","article-title":"Characteristics and prognostic impact of IDH mutations in AML: a COG, SWOG, and ECOG analysis","volume":"7","author":"Zarnegar-Lumley","year":"2023","journal-title":"Blood Adv"},{"issue":"1","key":"2025120616330519100_hem2025000714C33","doi-asserted-by":"crossref","first-page":"1580","DOI":"10.1182\/blood-2023-186458","article-title":"Characterization of the molecular landscape of pediatric acute myeloid leukemia: a retrospective AIEOP AML2013\/01 study","volume":"142","author":"Benetton","year":"2023","journal-title":"Blood"},{"issue":"26","key":"2025120616330519100_hem2025000714C34","doi-asserted-by":"crossref","first-page":"6558","DOI":"10.1182\/blood-2008-10-184747","article-title":"Prevalence and prognostic implications of CEBPA mutations in pediatric acute myeloid leukemia (AML): a report from the Children's Oncology Group","volume":"113","author":"Ho","year":"2009","journal-title":"Blood"},{"issue":"13","key":"2025120616330519100_hem2025000714C35","doi-asserted-by":"crossref","first-page":"1137","DOI":"10.1182\/blood.2020009652","article-title":"CEBPA-bZip mutations are associated with favorable prognosis in de novo AML: a report from the Children's Oncology Group","volume":"138","author":"Tarlock","year":"2021","journal-title":"Blood"},{"key":"2025120616330519100_hem2025000714C36","first-page":"100386","article-title":"Location, location, location: A mini-review of CEBPA variants in patients with acute myeloid leukemia","volume":"20","author":"Faisal","year":"2023","journal-title":"Leuk Res Rep"},{"issue":"18","key":"2025120616330519100_hem2025000714C37","doi-asserted-by":"crossref","first-page":"1603","DOI":"10.1182\/blood.2019004179","article-title":"Prognostic impact of CSF3R mutations in favorable risk childhood acute myeloid leukemia","volume":"135","author":"Tarlock","year":"2020","journal-title":"Blood"},{"issue":"8","key":"2025120616330519100_hem2025000714C38","first-page":"2459","article-title":"UBTF tandem duplications in pediatric myelodysplastic syndrome and acute myeloid leukemia: implications for clinical screening and diagnosis","volume":"109","author":"Barajas","year":"2024","journal-title":"Haematologica"},{"issue":"1","key":"2025120616330519100_hem2025000714C39","doi-asserted-by":"crossref","first-page":"2727","DOI":"10.1182\/blood-2019-126263","article-title":"Clinical features of pediatric acute myeloid leukemia with TP53 and CDKN2A\/2B copy number alterations","volume":"134","author":"Hara","year":"2019","journal-title":"Blood"},{"key":"2025120616330519100_hem2025000714C40","doi-asserted-by":"crossref","first-page":"975819","DOI":"10.3389\/fped.2022.975819","article-title":"Epigenetic modifications and targeted therapy in pediatric acute myeloid leukemia","volume":"10","author":"Xu","year":"2022","journal-title":"Front Pediatr"},{"key":"2025120616330519100_hem2025000714C41","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1182\/blood-2024-208864","article-title":"Comprehensive characterization of rare recurrent mutations in pediatric AML","volume":"144","author":"Lamble","year":"2024","journal-title":"Blood"}],"container-title":["Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2025\/1\/270\/2469767\/270pigazzi.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/ashpublications.org\/hematology\/article-pdf\/2025\/1\/270\/2469767\/270pigazzi.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,6]],"date-time":"2025-12-06T21:33:15Z","timestamp":1765056795000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/hematology\/article\/2025\/1\/270\/556893\/Using-genomics-to-refine-pediatric-AML-risk"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,5]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12,5]]},"published-print":{"date-parts":[[2025,12,5]]}},"URL":"https:\/\/doi.org\/10.1182\/hematology.2025000714","relation":{},"ISSN":["1520-4391","1520-4383"],"issn-type":[{"value":"1520-4391","type":"print"},{"value":"1520-4383","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,12,5]]},"published":{"date-parts":[[2025,12,5]]}}}