{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T01:31:24Z","timestamp":1785893484802,"version":"3.56.0"},"reference-count":41,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006668","name":"Fondo para La Investigaci\u00f3n Cient\u00edfica y Tecnol\u00f3gica","doi-asserted-by":"publisher","award":["PICT 2017-1186 PICT 2020-00326"],"award-info":[{"award-number":["PICT 2017-1186 PICT 2020-00326"]}],"id":[{"id":"10.13039\/501100006668","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Acute lymphoblastic leukemia is the most common childhood cancer, yet its diagnosis and risk classification remain incomplete in many regions due to limited access to molecular studies.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We present the first comprehensive genetic and molecular characterization of childhood B-cell Acute lymphoblastic leukemia in Argentina using whole-transcriptome sequencing of diagnostic bone marrow samples from 32 patients enrolled in the international clinical protocol ALLIC-BFM-2009.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>By integrating publicly available bioinformatic tools, we achieved molecular subtyping in over 93% of cases, a significant increase from the 31% rate attained through traditional methods. Our analysis revealed a diverse landscape of known and novel genetic alterations, including gene fusions, single nucleotide variants, and gene expression signatures relevant to prognosis and therapy. Importantly, we identified novel single nucleotide variants in DUX4, CSF3R and CREBBP, and fusion transcripts.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study not only reports transcriptional heterogeneity in our Latin American cohort but also supports the implementation of open-source bioinformatic pipelines in resource-limited settings to enhance precision diagnosis and guide personalized treatment.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2025.1701680","type":"journal-article","created":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T08:37:51Z","timestamp":1763368671000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Genetic characterization of pediatric B-cell acute lymphoblastic leukemia in Argentina uncovers molecular heterogeneity and novel variants"],"prefix":"10.3389","volume":"16","author":[{"given":"Mar\u00eda Sol","family":"Ruiz","sequence":"first","affiliation":[{"name":"CONICET - Universidad de Buenos Aires, Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN)","place":["Buenos Aires, Argentina"]},{"name":"Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Qu\u00edmica Biol\u00f3gica, Laboratorio de Inflamaci\u00f3n y C\u00e1ncer","place":["Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ezequiel","family":"Sosa","sequence":"additional","affiliation":[{"name":"CONICET - Universidad de Buenos Aires, Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN)","place":["Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Avenda\u00f1o","sequence":"additional","affiliation":[{"name":"CONICET - Universidad de Buenos Aires, Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN)","place":["Buenos Aires, Argentina"]},{"name":"Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Qu\u00edmica Biol\u00f3gica, Laboratorio de Inflamaci\u00f3n y C\u00e1ncer","place":["Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Gomez Mercado","sequence":"additional","affiliation":[{"name":"CONICET - Universidad de Buenos Aires, Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN)","place":["Buenos Aires, Argentina"]},{"name":"Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Qu\u00edmica Biol\u00f3gica, Laboratorio de Inflamaci\u00f3n y C\u00e1ncer","place":["Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Laura","family":"Lacreu","sequence":"additional","affiliation":[{"name":"CONICET - Universidad de Buenos Aires, Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN)","place":["Buenos Aires, Argentina"]},{"name":"Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Qu\u00edmica Biol\u00f3gica, Laboratorio de Inflamaci\u00f3n y C\u00e1ncer","place":["Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cecilia","family":"Riccheri","sequence":"additional","affiliation":[{"name":"Hospital Nacional Posadas, Servicio de Hemato-Oncolog\u00eda Pedi\u00e1trica","place":["Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginia","family":"Schuttenberg","sequence":"additional","affiliation":[{"name":"Hospital de Ni\u00f1os Sor Mar\u00eda Ludovica","place":["Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luis","family":"Aversa","sequence":"additional","affiliation":[{"name":"Hospital de Ni\u00f1os Ricardo Guti\u00e9rrez, Unidad de Hematolog\u00eda","place":["Ciudad Aut\u00f3noma de Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elba","family":"Vazquez","sequence":"additional","affiliation":[{"name":"CONICET - Universidad de Buenos Aires, Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN)","place":["Buenos Aires, Argentina"]},{"name":"Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Qu\u00edmica Biol\u00f3gica, Laboratorio de Inflamaci\u00f3n y C\u00e1ncer","place":["Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Geraldine","family":"Gueron","sequence":"additional","affiliation":[{"name":"CONICET - Universidad de Buenos Aires, Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN)","place":["Buenos Aires, Argentina"]},{"name":"Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Qu\u00edmica Biol\u00f3gica, Laboratorio de Inflamaci\u00f3n y C\u00e1ncer","place":["Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Javier","family":"Cotignola","sequence":"additional","affiliation":[{"name":"CONICET - Universidad de Buenos Aires, Instituto de Qu\u00edmica Biol\u00f3gica de la Facultad de Ciencias Exactas y Naturales (IQUIBICEN)","place":["Buenos Aires, Argentina"]},{"name":"Universidad de Buenos Aires, Facultad de Ciencias Exactas y Naturales, Departamento de Qu\u00edmica Biol\u00f3gica, Laboratorio de Inflamaci\u00f3n y C\u00e1ncer","place":["Buenos Aires, Argentina"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"578","DOI":"10.1158\/1055-9965.EPI-05-0833","article-title":"Cytogenetics of Hispanic and white children with acute lymphoblastic leukemia in California","volume":"15","author":"Aldrich","year":"2006","journal-title":"Cancer Epidemiol. Biomarkers Prev."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1023","DOI":"10.1016\/S0140-6736(17)33326-3","article-title":"Global surveillance of trends in cancer survival 2000-14 (CONCORD-3): analysis of individual records for 37\u2008513\u2008025 patients diagnosed with one of 18 cancers from 322 population-based registries in 71 countries","volume":"391","author":"Allemani","year":"2018","journal-title":"Lancet Lond. Engl."},{"key":"B3","doi-asserted-by":"publisher","first-page":"e939","DOI":"10.1097\/HS9.0000000000000939","article-title":"The gene expression classifier ALLCatchR identifies B-cell precursor ALL subtypes and underlying developmental trajectories across age","volume":"7","author":"Beder","year":"2023","journal-title":"HemaSphere"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2014\/210560","article-title":"Prevalence of gene rearrangements in Mexican children with acute lymphoblastic leukemia: a population study\u2014report from the Mexican interinstitutional group for the identification of the causes of childhood leukemia","volume":"2014","author":"Bekker-M\u00e9ndez","year":"2014","journal-title":"Biomed. Res. Int."},{"key":"B5","doi-asserted-by":"publisher","first-page":"1376","DOI":"10.1038\/s41588-022-01159-z","article-title":"The genomic landscape of pediatric acute lymphoblastic leukemia","volume":"54","author":"Brady","year":"2022","journal-title":"Nat. Genet."},{"key":"B6","doi-asserted-by":"publisher","first-page":"525","DOI":"10.1038\/nbt.3519","article-title":"Near-optimal probabilistic RNA-Seq quantification","volume":"34","author":"Bray","year":"2016","journal-title":"Nat. Biotechnol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"3499","DOI":"10.1200\/JCO.22.01760","article-title":"Childhood acute lymphoblastic leukemia: results of the randomized acute lymphoblastic leukemia intercontinental-berlin-frankfurt-m\u00fcnster 2009 trial","volume":"41","author":"Campbell","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"5063","DOI":"10.1002\/cncr.25406","article-title":"Childhood cancer mortality in America, Asia, and oceania, 1970 through 2007","volume":"116","author":"Chatenoud","year":"2010","journal-title":"Cancer"},{"key":"B9","doi-asserted-by":"publisher","first-page":"193","DOI":"10.1159\/000441046","article-title":"Cytogenetic and molecular findings in children with acute lymphoblastic leukemia: experience of a single institution in Argentina","volume":"6","author":"Cocc\u00e9","year":"2015","journal-title":"Mol. Syndromol."},{"key":"B10","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1007\/s00428-022-03448-8","article-title":"International consensus classification of acute lymphoblastic leukemia\/lymphoma","volume":"482","author":"Duffield","year":"2023","journal-title":"Virchows Arch."},{"key":"B11","doi-asserted-by":"publisher","first-page":"3283","DOI":"10.3390\/cancers14133283","article-title":"Impact of IKZF1 deletions in the prognosis of childhood acute lymphoblastic leukemia in Argentina","volume":"14","author":"Felice","year":"2022","journal-title":"Cancers"},{"key":"B12","doi-asserted-by":"publisher","first-page":"e202402144","DOI":"10.1083\/jcb.202402144","article-title":"DBF4, not DRF1, is the crucial regulator of CDC7 kinase at replication forks","volume":"223","author":"G\u00f6der","year":"2024","journal-title":"J. Cell Biol."},{"key":"B13","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1038\/s41588-018-0315-5","article-title":"PAX5-driven subtypes of B-progenitor acute lymphoblastic leukemia","volume":"51","author":"Gu","year":"2019","journal-title":"Nat. Genet."},{"key":"B14","doi-asserted-by":"publisher","first-page":"e290","DOI":"10.3324\/haematol.2019.230821","article-title":"RNAmut: robust identification of somatic mutations in acute myeloid leukemia using RNA-Sequencing","volume":"105","author":"Gu","year":"2020","journal-title":"Haematologica"},{"key":"B15","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1186\/s13059-019-1842-9","article-title":"Accuracy assessment of fusion transcript detection via read-mapping and de novo fusion transcript assembly-based methods","volume":"20","author":"Haas","year":"2019","journal-title":"Genome Biol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"100467","DOI":"10.1016\/j.crmeth.2023.100467","article-title":"Targeted in silico characterization of fusion transcripts in tumor and normal tissues via FusionInspector","volume":"3","author":"Haas","year":"2023","journal-title":"Cell Rep. Methods"},{"key":"B17","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1038\/ng.3844","article-title":"Conserved roles of mouse DUX and human DUX4 in activating cleavage-stage genes and MERVL\/HERVL retrotransposons","volume":"49","author":"Hendrickson","year":"2017","journal-title":"Nat. Genet."},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.22541\/au.172503790.03499255\/v1","article-title":"Analysis of the clinical characteristics of 28 children with NF1 mutation-positive acute leukemia and literature review","author":"Huang","year":"2024"},{"key":"B19","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1158\/2643-3230.BCD-20-0229","article-title":"Clinical significance of novel subtypes of acute lymphoblastic leukemia in the context of minimal residual disease\u2013directed therapy","volume":"2","author":"Jeha","year":"2021","journal-title":"Blood Cancer Discov."},{"key":"B20","doi-asserted-by":"publisher","first-page":"100405","DOI":"10.1016\/j.lrr.2023.100405","article-title":"Epidemiological and clinical characteristics of adult acute lymphoblastic leukemia patients in Chile: a single-center analysis","volume":"21","author":"Jerez","year":"2024","journal-title":"Leuk. Res. Rep."},{"key":"B21","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1001\/jamaoncol.2021.6826","article-title":"Association of genetic ancestry with the molecular subtypes and prognosis of childhood acute lymphoblastic leukemia","volume":"8","author":"Lee","year":"2022","journal-title":"JAMA Oncol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"1781","DOI":"10.1056\/NEJMoa1214514","article-title":"Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CML","volume":"368","author":"Maxson","year":"2013","journal-title":"N. Engl. J. Med."},{"key":"B23","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1200\/EDBK_278171","article-title":"Cutting to the front of the line: immunotherapy for childhood acute lymphoblastic leukemia","volume":"40","author":"McNeer","year":"2020","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"B24","doi-asserted-by":"publisher","first-page":"2957","DOI":"10.1182\/bloodadvances.2022009179","article-title":"Classification and genetics of pediatric B-other acute lymphoblastic leukemia by targeted RNA sequencing","volume":"7","author":"Migita","year":"2023","journal-title":"Blood Adv."},{"key":"B25","volume-title":"Registro oncopedi\u00e1trico argentino (ROHA)","author":"Moreno","year":"2021"},{"key":"B26","doi-asserted-by":"publisher","first-page":"1334","DOI":"10.2174\/1381612828666220324141016","article-title":"FER1L4: a long non-coding RNA with multiple roles in the occurrence andDevelopment of tumors","volume":"28","author":"Mou","year":"2022","journal-title":"Curr. Pharm. Des."},{"key":"B27","doi-asserted-by":"publisher","first-page":"235","DOI":"10.1038\/nature09727","article-title":"CREBBP mutations in relapsed acute lymphoblastic leukaemia","volume":"471","author":"Mullighan","year":"2011","journal-title":"Nature"},{"key":"B28","doi-asserted-by":"publisher","first-page":"128","DOI":"10.3324\/haematol.2017.186320","article-title":"Clinical and molecular characteristics of MEF2D fusion-positive B-cell precursor acute lymphoblastic leukemia in childhood, including a novel translocation resulting in MEF2D-HNRNPH1 gene fusion","volume":"104","author":"Ohki","year":"2019","journal-title":"Haematologica"},{"key":"B29","doi-asserted-by":"publisher","first-page":"e26909","DOI":"10.1002\/pbc.26909","article-title":"Treatment-related mortality in relapsed childhood acute lymphoblastic leukemia","volume":"65","author":"Oskarsson","year":"2018","journal-title":"Pediatr. Blood Cancer"},{"key":"B30","doi-asserted-by":"publisher","first-page":"440","DOI":"10.1016\/S2352-4642(18)30066-X","article-title":"Global efforts toward the cure of childhood acute lymphoblastic leukaemia","volume":"2","author":"Pui","year":"2018","journal-title":"Lancet Child. Adolesc. Health"},{"key":"B31","doi-asserted-by":"publisher","first-page":"3482","DOI":"10.1200\/JCO.23.00451","article-title":"Optimizing pediatric leukemia care in countries with limited resources","volume":"41","author":"Ribeiro","year":"2023","journal-title":"J. Clin. Oncol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1038\/s41408-019-0239-z","article-title":"Characterization of TCF3 rearrangements in pediatric B-lymphoblastic leukemia\/lymphoma by mate-pair sequencing (MPseq) identifies complex genomic rearrangements and a novel TCF3\/TEF gene fusion","volume":"9","author":"Rowsey","year":"2019","journal-title":"Blood Cancer J."},{"key":"B33","doi-asserted-by":"publisher","first-page":"4093","DOI":"10.1182\/bloodadvances.2021005894","article-title":"ALLSorts: an RNA-seq subtype classifier for B-cell acute lymphoblastic leukemia","volume":"6","author":"Schmidt","year":"2022","journal-title":"Blood Adv."},{"key":"B34","doi-asserted-by":"publisher","first-page":"100208","DOI":"10.1016\/j.lrr.2020.100208","article-title":"CSF3R truncation mutations in a patient with B-cell acute lymphoblastic leukemia and a favorable response to chemotherapy plus dasatinib","volume":"14","author":"Schwartz","year":"2020","journal-title":"Leuk. Res. Rep."},{"key":"B35","doi-asserted-by":"publisher","first-page":"3451","DOI":"10.1200\/JCO.2016.66.5547","article-title":"MEF2D - BCL9 fusion gene is associated with high-risk acute B-Cell precursor lymphoblastic leukemia in adolescents","volume":"34","author":"Suzuki","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"B36","doi-asserted-by":"publisher","first-page":"2339","DOI":"10.1200\/JCO.2009.25.1983","article-title":"Long-term outcome in children with relapsed acute lymphoblastic leukemia after time-point and site-of-relapse stratification and intensified short-course multidrug chemotherapy: results of trial ALL-REZ BFM 90","volume":"28","author":"Tallen","year":"2010","journal-title":"J. Clin. Oncol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"2789","DOI":"10.1038\/s41467-019-10637-8","article-title":"Long-read sequencing unveils IGH-DUX4 translocation into the silenced IGH allele in B-cell acute lymphoblastic leukemia","volume":"10","author":"Tian","year":"2019","journal-title":"Nat. Commun."},{"key":"B38","doi-asserted-by":"publisher","first-page":"5269","DOI":"10.1182\/bloodadvances.2020002013","article-title":"Heterozygous germ line CSF3R variants as risk alleles for development of hematologic malignancies","volume":"4","author":"Trottier","year":"2020","journal-title":"Blood Adv."},{"key":"B39","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1038\/s41419-020-03040-5","article-title":"EFTUD2 maintains the survival of tumor cells and promotes hepatocellular carcinoma progression via the activation of STAT3","volume":"11","author":"Tu","year":"2020","journal-title":"Cell Death Dis."},{"key":"B40","doi-asserted-by":"publisher","first-page":"1141310","DOI":"10.3389\/fmolb.2023.1141310","article-title":"Fusion InPipe, an integrative pipeline for gene fusion detection from RNA-seq data in acute pediatric leukemia","volume":"10","author":"Vicente-Garc\u00e9s","year":"2023","journal-title":"Front. Mol. Biosci."},{"key":"B41","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1007\/s11596-021-2477-0","article-title":"Cytogenetic characteristics of childhood acute lymphoblastic leukemia: a study of 1541 Chinese patients newly diagnosed between 2001 and 2014","volume":"42","author":"Yin","year":"2022","journal-title":"Curr. Med. Sci."}],"container-title":["Frontiers in Pharmacology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1701680\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T09:45:59Z","timestamp":1770975959000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fphar.2025.1701680\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,17]]},"references-count":41,"alternative-id":["10.3389\/fphar.2025.1701680"],"URL":"https:\/\/doi.org\/10.3389\/fphar.2025.1701680","relation":{},"ISSN":["1663-9812"],"issn-type":[{"value":"1663-9812","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,17]]},"article-number":"1701680"}}