{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:26:58Z","timestamp":1790713618398,"version":"4.1.0"},"reference-count":61,"publisher":"American Society of Hematology","issue":"10","license":[{"start":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T00:00:00Z","timestamp":1670544000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,3,9]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Gain of chromosome 21 (Hsa21) is among the most frequent aneuploidies in leukemia. However, it remains unclear how partial or complete amplifications of Hsa21 promote leukemogenesis and why children with Down syndrome (DS) (ie, trisomy 21) are particularly at risk of leukemia development. Here, we propose that RUNX1 isoform disequilibrium with RUNX1A bias is key to DS-associated myeloid leukemia (ML-DS). Starting with Hsa21-focused CRISPR\u2013CRISPR-associated protein 9 screens, we uncovered a strong and specific RUNX1 dependency in ML-DS cells. Expression of the RUNX1A isoform is elevated in patients with ML-DS, and mechanistic studies using murine ML-DS models and patient-derived xenografts revealed that excess RUNX1A synergizes with the pathognomonic Gata1s mutation during leukemogenesis by displacing RUNX1C from its endogenous binding sites and inducing oncogenic programs in complex with the MYC cofactor MAX. These effects were reversed by restoring the RUNX1A:RUNX1C equilibrium in patient-derived xenografts in\u00a0vitro and in\u00a0vivo. Moreover, pharmacological interference with MYC:MAX dimerization using MYCi361 exerted strong antileukemic effects. Thus, our study highlights the importance of alternative splicing in leukemogenesis, even on a background of aneuploidy, and paves the way for the development of specific and targeted therapies for ML-DS, as well as for other leukemias with Hsa21 aneuploidy or RUNX1 isoform disequilibrium.<\/jats:p>","DOI":"10.1182\/blood.2022017619","type":"journal-article","created":{"date-parts":[[2022,12,9]],"date-time":"2022-12-09T16:07:17Z","timestamp":1670602037000},"page":"1105-1118","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":50,"title":["<i>RUNX1<\/i>\n                    isoform disequilibrium promotes the\u00a0development of trisomy 21\u2013associated myeloid\u00a0leukemia"],"prefix":"10.1182","volume":"141","author":[{"given":"Sofia","family":"Gialesaki","sequence":"first","affiliation":[{"name":"1Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9200-5455","authenticated-orcid":false,"given":"Daniela","family":"Br\u00e4uer-Hartmann","sequence":"additional","affiliation":[{"name":"2Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, Halle, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hasan","family":"Issa","sequence":"additional","affiliation":[{"name":"3Department of Pediatrics, Goethe University Frankfurt, Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raj","family":"Bhayadia","sequence":"additional","affiliation":[{"name":"3Department of Pediatrics, Goethe University Frankfurt, Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oriol","family":"Alejo-Valle","sequence":"additional","affiliation":[{"name":"2Pediatric Hematology and Oncology, Martin Luther University Halle-Wittenberg, 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Pediatrics, Goethe University Frankfurt, Frankfurt am Main, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Ihling","sequence":"additional","affiliation":[{"name":"5Department of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Sinz","sequence":"additional","affiliation":[{"name":"5Department of Pharmaceutical Chemistry and Bioanalytics, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Halle, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2718-8907","authenticated-orcid":false,"given":"Markus","family":"Gla\u00df","sequence":"additional","affiliation":[{"name":"6Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"H\u00fcttelmaier","sequence":"additional","affiliation":[{"name":"6Institute of Molecular Medicine, Martin Luther University Halle-Wittenberg, Halle, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00f6ren","family":"Matzk","sequence":"additional","affiliation":[{"name":"4Max Planck Institute for Molecular Genetics, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lena","family":"Schmid","sequence":"additional","affiliation":[{"name":"1Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7712-1300","authenticated-orcid":false,"given":"Farina Josepha","family":"Str\u00fcwe","sequence":"additional","affiliation":[{"name":"1Pediatric Hematology and Oncology, Hannover Medical School, Hannover, 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