{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,27]],"date-time":"2026-06-27T22:50:29Z","timestamp":1782600629622,"version":"3.54.5"},"reference-count":54,"publisher":"American Society of Hematology","issue":"19","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2023,10,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Large-scale compound screens are a powerful model system for understanding variability of treatment response and discovering druggable tumor vulnerabilities of hematological malignancies. However, as mostly performed in a monoculture of tumor cells, these assays disregard modulatory effects of the in\u00a0vivo microenvironment. It is an open question whether and to what extent coculture with bone marrow stromal cells could improve the biological relevance of drug testing assays over monoculture. Here, we established a high-throughput platform to measure ex\u00a0vivo sensitivity of 108 primary blood cancer samples to 50 drugs in monoculture and coculture with bone marrow stromal cells. Stromal coculture conferred resistance to 52% of compounds in chronic lymphocytic leukemia (CLL) and 36% of compounds in acute myeloid leukemia (AML), including chemotherapeutics, B\u2013cell receptor inhibitors, proteasome inhibitors, and Bromodomain and extraterminal domain inhibitors. Only the JAK inhibitors ruxolitinib and tofacitinib exhibited increased efficacy in AML and CLL stromal coculture. We further confirmed the importance of JAK-STAT signaling for stroma-mediated resistance by showing that stromal cells induce phosphorylation of STAT3 in CLL cells. We genetically characterized the 108 cancer samples and found that drug-gene associations strongly correlated between monoculture and coculture. However, effect sizes were lower in coculture, with more drug-gene associations detected in monoculture than in coculture. Our results justify a 2-step strategy for drug perturbation testing, with large-scale screening performed in monoculture, followed by focused evaluation of potential stroma-mediated resistances in coculture.<\/jats:p>","DOI":"10.1182\/bloodadvances.2022009652","type":"journal-article","created":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T12:44:17Z","timestamp":1687610657000},"page":"5925-5936","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":10,"title":["Comparing the value of mono- vs coculture for high-throughput compound screening in hematological malignancies"],"prefix":"10.1182","volume":"7","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8502-0366","authenticated-orcid":false,"given":"Sophie A.","family":"Herbst","sequence":"first","affiliation":[{"name":"1Department of Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany"},{"name":"2Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany"},{"name":"3Molecular Medicine Partnership Unit, Heidelberg, Germany"},{"name":"4Department of Translational Medical Oncology, National Center for Tumor Diseases Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany"},{"name":"5Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5061-7285","authenticated-orcid":false,"given":"Vladislav","family":"Kim","sequence":"additional","affiliation":[{"name":"2Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany"},{"name":"3Molecular Medicine Partnership Unit, Heidelberg, Germany"},{"name":"5Faculty of Biosciences, University of Heidelberg, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6973-3531","authenticated-orcid":false,"given":"Tobias","family":"Roider","sequence":"additional","affiliation":[{"name":"1Department of Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany"},{"name":"2Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany"},{"name":"3Molecular Medicine Partnership Unit, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva C.","family":"Schitter","sequence":"additional","affiliation":[{"name":"1Department of Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9992-3109","authenticated-orcid":false,"given":"Peter-Martin","family":"Bruch","sequence":"additional","affiliation":[{"name":"1Department of Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany"},{"name":"2Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany"},{"name":"3Molecular Medicine Partnership Unit, Heidelberg, Germany"},{"name":"6Department of Hematology and Oncology, University Hospital D\u00fcsseldorf, D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nora","family":"Liebers","sequence":"additional","affiliation":[{"name":"1Department of Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany"},{"name":"2Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany"},{"name":"3Molecular Medicine Partnership Unit, Heidelberg, Germany"},{"name":"4Department of Translational Medical Oncology, National Center for Tumor Diseases Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolin","family":"Kolb","sequence":"additional","affiliation":[{"name":"1Department of Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mareike","family":"Knoll","sequence":"additional","affiliation":[{"name":"1Department of Medicine V, Hematology, Oncology and Rheumatology, Heidelberg University Hospital, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junyan","family":"Lu","sequence":"additional","affiliation":[{"name":"2Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany"},{"name":"3Molecular Medicine Partnership Unit, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter","family":"Dreger","sequence":"additional","affiliation":[{"name":"1Department of Medicine V, Hematology, Oncology and 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