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  • Malyukova, AlenaKarolinska Inst, Sweden,Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden (author)

Combination of tyrosine kinase inhibitors and the MCL1 inhibitor S63845 exerts synergistic antitumorigenic effects on CML cells

  • Article/chapterEnglish2021

Publisher, publication year, extent ...

  • 2021-09-25
  • Springer Nature,2021
  • electronicrdacarrier

Numbers

  • LIBRIS-ID:oai:DiVA.org:liu-179852
  • https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-179852URI
  • https://doi.org/10.1038/s41419-021-04154-0DOI
  • http://kipublications.ki.se/Default.aspx?queryparsed=id:147653913URI
  • https://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-188158URI

Supplementary language notes

  • Language:English
  • Summary in:English

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  • Subject category:ref swepub-contenttype
  • Subject category:art swepub-publicationtype

Notes

  • Funding Agencies|Cancer Research Funds of Radiumhemmet [174283]; Thorsmans Stiftelse for Pre-leukemi Forskning; Gunnar Grimfors Gavofond for Hematologisk Forskning; Cathrine Everts Research Foundation; Lars Hierta Memorial Foundation; Emil Anderson Fund for Medical Research; Swedish Research CouncilSwedish Research CouncilEuropean Commission [2013-08807]; Karolinska Institute Foundation and Funds; Karolinska InstituteKarolinska Institutet
  • Tyrosine kinase inhibitor (TKI) treatment has dramatically improved the survival of chronic myeloid leukemia (CML) patients, but measurable residual disease typically persists. To more effectively eradicate leukemia cells, simultaneous targeting of BCR-ABL1 and additional CML-related survival proteins has been proposed. Notably, several highly specific myeloid cell leukemia 1 (MCL1) inhibitors have recently entered clinical trials for various hematologic malignancies, although not for CML, reflecting the insensitivity of CML cell lines to single MCL1 inhibition. Here, we show that combining TKI (imatinib, nilotinib, dasatinib, or asciminib) treatment with the small-molecule MCL1 inhibitor S63845 exerted strong synergistic antiviability and proapoptotic effects on CML lines and CD34+ stem/progenitor cells isolated from untreated CML patients in chronic phase. Using wild-type BCR-ABL1-harboring CML lines and their T315I-mutated sublines (generated by CRISPR/Cas9-mediated homologous recombination), we prove that the synergistic proapoptotic effect of the drug combination depended on TKI-mediated BCR-ABL1 inhibition, but not on TKI-related off-target mechanisms. Moreover, we demonstrate that colony formation of CML but not normal hematopoietic stem/progenitor cells became markedly reduced upon combination treatment compared to imatinib monotherapy. Our results suggest that dual targeting of MCL1 and BCR-ABL1 activity may efficiently eradicate residual CML cells without affecting normal hematopoietic stem/progenitors.

Subject headings and genre

Added entries (persons, corporate bodies, meetings, titles ...)

  • Ujvari, DorinaKarolinska Institutet,Department of Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden (author)
  • Yektaei-Karin, ElhamKarolinska Inst, Sweden,Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden (author)
  • Zovko, AnaKarolinska Inst, Sweden,Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden (author)
  • Madapura, Harsha S.Karolinska Inst, Sweden,Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden (author)
  • Keszei, MartonKarolinska Institutet,Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden (author)
  • Nagy, NoemiKarolinska Institutet,Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden (author)
  • Lotfi, Kourosh,1966-Linköpings universitet,Medicinska fakulteten,Avdelningen för klinisk kemi och farmakologi,Region Östergötland, Hematologiska kliniken US,Department of Hematology, Linköping University Hospital, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden(Swepub:liu)koulo97 (author)
  • Björn, NiclasLinköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten,Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden(Swepub:liu)nikbj02 (author)
  • Wallvik, JonasUmeå universitet,Avdelningen för medicin(Swepub:umu)jowa0061 (author)
  • Tamai, MinoriUniv Yamanashi, Japan,Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan (author)
  • Nguyen, Thao T. T.Univ Yamanashi, Japan,Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan (author)
  • Akahane, KoshiUniv Yamanashi, Japan,Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan (author)
  • Inukai, TakeshiUniv Yamanashi, Japan,Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan (author)
  • Stenke, LeifKarolinska Institutet,Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden; Division of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden (author)
  • Salamon, DanielKarolinska Institutet,Department of Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden (author)
  • Karolinska Inst, SwedenDepartment of Medicine Solna, Karolinska Institute, Stockholm, Sweden (creator_code:org_t)

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