{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,2]],"date-time":"2026-11-02T18:31:15Z","timestamp":1793644275946,"version":"4.5.1"},"reference-count":81,"publisher":"American Society of Hematology","issue":"13","license":[{"start":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T00:00:00Z","timestamp":1670803200000},"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":[[2023,3,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Myeloid neoplasms with erythroid or megakaryocytic differentiation include pure erythroid leukemia, myelodysplastic syndrome with erythroid features, and acute megakaryoblastic leukemia (FAB M7) and are characterized by poor prognosis and limited treatment options. Here, we investigate the drug sensitivity landscape of these rare malignancies. We show that acute myeloid leukemia (AML) cells with erythroid or megakaryocytic differentiation depend on the antiapoptotic protein B-cell lymphoma (BCL)-XL, rather than BCL-2, using combined ex\u00a0vivo drug sensitivity testing, genetic perturbation, and transcriptomic profiling. High-throughput screening of &amp;gt;500 compounds identified the BCL-XL\u2013selective inhibitor A-1331852 and navitoclax as highly effective against erythroid\/megakaryoblastic leukemia cell lines. In contrast, these AML subtypes were resistant to the BCL-2 inhibitor venetoclax, which is used clinically in the treatment of AML. Consistently, genome-scale CRISPR-Cas9 and RNAi screening data demonstrated the striking essentiality of BCL-XL-encoding BCL2L1 but not BCL2 or MCL1, for the survival of erythroid\/megakaryoblastic leukemia cell lines. Single-cell and bulk transcriptomics of patient samples with erythroid and megakaryoblastic leukemias identified high BCL2L1 expression compared with other subtypes of AML and other hematological malignancies, where BCL2 and MCL1 were more prominent. BCL-XL inhibition effectively killed blasts in samples from patients with AML with erythroid or megakaryocytic differentiation ex\u00a0vivo and reduced tumor burden in a mouse erythroleukemia xenograft model. Combining the BCL-XL inhibitor with the JAK inhibitor ruxolitinib showed synergistic and durable responses in cell lines. Our results suggest targeting BCL-XL as a potential therapy option in erythroid\/megakaryoblastic leukemias and highlight an AML subgroup with potentially reduced sensitivity to venetoclax-based treatments.<\/jats:p>","DOI":"10.1182\/blood.2021011094","type":"journal-article","created":{"date-parts":[[2022,12,12]],"date-time":"2022-12-12T20:58:17Z","timestamp":1670878697000},"page":"1610-1625","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":141,"title":["Erythroid\/megakaryocytic differentiation confers BCL-XL dependency and venetoclax resistance in acute myeloid leukemia"],"prefix":"10.1182","volume":"141","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1903-0408","authenticated-orcid":false,"given":"Heikki","family":"Kuusanm\u00e4ki","sequence":"first","affiliation":[{"name":"1Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland"},{"name":"2Biotech Research & Innovation Centre and Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, Denmark"},{"name":"3Foundation for the Finnish Cancer Institute, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8084-0282","authenticated-orcid":false,"given":"Olli","family":"Dufva","sequence":"additional","affiliation":[{"name":"4Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland"},{"name":"5Translational Immunology Research Program and Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland"},{"name":"6iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7764-7820","authenticated-orcid":false,"given":"Markus","family":"V\u00e4h\u00e4-Koskela","sequence":"additional","affiliation":[{"name":"1Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0849-1759","authenticated-orcid":false,"given":"Aino-Maija","family":"Lepp\u00e4","sequence":"additional","affiliation":[{"name":"1Institute for Molecular Medicine Finland, Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland"},{"name":"7Division of Stem Cells and Cancer, German Cancer Research Center and DKFZ-ZMBH Alliance, Heidelberg, 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