{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T07:31:54Z","timestamp":1784878314408,"version":"3.55.0"},"reference-count":73,"publisher":"Wiley","issue":"8","license":[{"start":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T00:00:00Z","timestamp":1755561600000},"content-version":"vor","delay-in-days":18,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["HemaSphere"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Acute leukemia of ambiguous lineage (ALAL) is a rare, poor\u2010prognosis acute leukemia subtype that cannot be assigned to a single hematopoietic lineage. Although ALAL patients are typically treated with acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) regimens, optimal treatment choice is hindered by their lineage ambiguity. Therefore, we investigated the added value of transcriptomics for improving lineage assignment, currently based mainly on surface markers. First, we used an in\u2010house pipeline to detect genetic lesions in RNA sequencing data (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200930) with a sensitivity\u2009&gt;\u200990% for small variants. Second, we compared ALAL gene expression profiles (GEPs) with representative AML (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009145), B\u2010ALL (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009223), and T\u2010ALL (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200985) cases. In a principal component analysis (PCA), ALALs did not form a clear separate group, as most clustered with AML, B\u2010ALL, or T\u2010ALL. Accordingly, a machine learning classifier trained with GEPs of acute leukemias segregated 27\/30 ALALs into myeloid\u2010, B\u2010, or T\u2010lymphoid. These 27 cases harbored genetic abnormalities consistent with the classifier\u2010assigned leukemia. Furthermore, deconvolution of ALAL GEPs revealed enrichment for signatures of normal hematopoietic cells corresponding to the leukemic type predicted by our algorithm. The classifier was also applied on an external ALAL cohort (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u200924), assigning 75% of the patients to a lineage matching their immunophenotypic and methylation profiles. In conclusion, integrative analysis of RNA sequencing data can accurately classify most ALAL cases as lineage\u2010defined, while others show true transcriptional and epigenetic ambiguity driven by lesions like\n                    <jats:italic>BCL11B<\/jats:italic>\n                    . The pipeline and classifier developed here are valuable tools to improve ALAL diagnosis and guide therapeutic decisions.\n                  <\/jats:p>","DOI":"10.1002\/hem3.70195","type":"journal-article","created":{"date-parts":[[2025,8,19]],"date-time":"2025-08-19T09:49:56Z","timestamp":1755596996000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Transcriptional profiling directs the classification of acute leukemias of ambiguous lineage into AML, B\u2010ALL, or T\u2010ALL"],"prefix":"10.1002","volume":"9","author":[{"given":"Roger","family":"Mulet\u2010Lazaro","sequence":"first","affiliation":[{"name":"Department of Hematology Erasmus University Medical Center, Erasmus MC Cancer Institute Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anik\u00f3","family":"Sijs\u2010Szab\u00f3","sequence":"additional","affiliation":[{"name":"Department of Hematology Erasmus University Medical Center, Erasmus MC Cancer Institute Rotterdam The Netherlands"},{"name":"Department of Hematology Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remco M.","family":"Hoogenboezem","sequence":"additional","affiliation":[{"name":"Department of Hematology Erasmus University Medical Center, Erasmus MC Cancer Institute Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stanley","family":"van Herk","sequence":"additional","affiliation":[{"name":"Department of Hematology Erasmus University Medical Center, Erasmus MC Cancer Institute Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Exalto","sequence":"additional","affiliation":[{"name":"Department of Hematology Erasmus University Medical Center, Erasmus MC Cancer Institute Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jasper E.","family":"Koenders","sequence":"additional","affiliation":[{"name":"Department of Hematology Erasmus University Medical Center, Erasmus MC Cancer Institute Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patricia G.","family":"Hoogeveen","sequence":"additional","affiliation":[{"name":"Department of Immunology Erasmus University Medical Center Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7ois G.","family":"Kavelaars","sequence":"additional","affiliation":[{"name":"Department of Hematology Erasmus University Medical Center, Erasmus MC Cancer Institute Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita M.","family":"Schelen","sequence":"additional","affiliation":[{"name":"Department of Hematology Erasmus University Medical Center, Erasmus MC Cancer Institute Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willemijn","family":"van den Ancker","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam University Medical Center Free University Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arjan A.","family":"van de Loosdrecht","sequence":"additional","affiliation":[{"name":"Department of Hematology, Amsterdam University Medical Center Free University Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles G.","family":"Mullighan","sequence":"additional","affiliation":[{"name":"Department of Pathology St. Jude Children's Research Hospital Memphis Tennessee USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. Berna","family":"Beverloo","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Erasmus University Medical Center Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vincent","family":"van der Velden","sequence":"additional","affiliation":[{"name":"Department of Immunology Erasmus University Medical Center Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan J.","family":"Cornelissen","sequence":"additional","affiliation":[{"name":"Department of Hematology Erasmus University Medical Center, Erasmus MC Cancer Institute Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J. 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