{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,7]],"date-time":"2026-11-07T05:24:22Z","timestamp":1794029062877,"version":"4.8.0"},"reference-count":42,"publisher":"American Society of Hematology","issue":"24","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,12,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>BCL-2 inhibition has been shown to be effective in acute myeloid leukemia (AML) in combination with hypomethylating agents or low-dose cytarabine. However, resistance and relapse represent major clinical challenges. Therefore, there is an unmet need to overcome resistance to current venetoclax-based strategies. We performed high-throughput drug screening to identify effective combination partners for venetoclax in AML. Overall, 64 antileukemic drugs were screened in 31 primary high-risk AML samples with or without venetoclax. Gilteritinib exhibited the highest synergy with venetoclax in FLT3 wild-type AML. The combination of gilteritinib and venetoclax increased apoptosis, reduced viability, and was active in venetoclax-azacitidine\u2013resistant cell lines and primary patient samples. Proteomics revealed increased FLT3 wild-type signaling in specimens with low in vitro response to the currently used venetoclax-azacitidine combination. Mechanistically, venetoclax with gilteritinib decreased phosphorylation of ERK and GSK3B via combined AXL and FLT3 inhibition with subsequent suppression of the antiapoptotic protein MCL-1. MCL-1 downregulation was associated with increased MCL-1 phosphorylation of serine 159, decreased phosphorylation of threonine 161, and proteasomal degradation. Gilteritinib and venetoclax were active in an FLT3 wild-type AML patient-derived xenograft model with TP53 mutation and reduced leukemic burden in 4 patients with FLT3 wild-type AML receiving venetoclax-gilteritinib off label after developing refractory disease under venetoclax-azacitidine. In summary, our results suggest that combined inhibition of FLT3\/AXL potentiates venetoclax response in FLT3 wild-type AML by inducing MCL-1 degradation. Therefore, the venetoclax-gilteritinib combination merits testing as a potentially active regimen in patients with high-risk FLT3 wild-type AML.<\/jats:p>","DOI":"10.1182\/blood.2021014241","type":"journal-article","created":{"date-parts":[[2022,7,20]],"date-time":"2022-07-20T14:57:08Z","timestamp":1658329028000},"page":"2594-2610","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":105,"title":["Venetoclax synergizes with gilteritinib in FLT3 wild-type high-risk acute myeloid leukemia by suppressing MCL-1"],"prefix":"10.1182","volume":"140","author":[{"given":"Maike","family":"Janssen","sequence":"first","affiliation":[{"name":"1Department of Internal Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany"},{"name":"2Molecular Medicine Partnership Unit (MMPU), University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Schmidt","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, 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 Internal Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany"},{"name":"2Molecular Medicine Partnership Unit (MMPU), University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maximilian F.","family":"Blank","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany"},{"name":"2Molecular Medicine Partnership Unit (MMPU), University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany"},{"name":"3Division of Proteomics of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Rohde","sequence":"additional","affiliation":[{"name":"1Department of Internal Medicine V, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany"},{"name":"2Molecular Medicine Partnership Unit (MMPU), University of Heidelberg and European Molecular Biology Laboratory, Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Waclawiczek","sequence":"additional","affiliation":[{"name":"4Division of Stem Cells and Cancer, German Cancer Research Center, Heidelberg, 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