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Combination of tyro...
Combination of tyrosine kinase inhibitors and the MCL1 inhibitor S63845 exerts synergistic antitumorigenic effects on CML cells
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- Malyukova, Alena (författare)
- Karolinska Inst, Sweden,Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden
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- Ujvari, Dorina (författare)
- Karolinska Institutet,Department of Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden
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- Yektaei-Karin, Elham (författare)
- Karolinska Inst, Sweden,Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden
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- Zovko, Ana (författare)
- Karolinska Inst, Sweden,Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden
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- Madapura, Harsha S. (författare)
- Karolinska Inst, Sweden,Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
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- Keszei, Marton (författare)
- Karolinska Institutet,Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
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- Nagy, Noemi (författare)
- Karolinska Institutet,Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden
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- Lotfi, Kourosh, 1966- (författare)
- 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
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- Björn, Niclas (författare)
- Linköpings universitet,Avdelningen för klinisk kemi och farmakologi,Medicinska fakulteten,Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
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- Wallvik, Jonas (författare)
- Umeå universitet,Avdelningen för medicin
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- Tamai, Minori (författare)
- Univ Yamanashi, Japan,Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan
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- Nguyen, Thao T. T. (författare)
- Univ Yamanashi, Japan,Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan
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- Akahane, Koshi (författare)
- Univ Yamanashi, Japan,Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan
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- Inukai, Takeshi (författare)
- Univ Yamanashi, Japan,Department of Pediatrics, School of Medicine, University of Yamanashi, Chuo, Japan
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- Stenke, Leif (författare)
- Karolinska Institutet,Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden; Division of Hematology, Karolinska University Hospital Solna, Stockholm, Sweden
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- Salamon, Daniel (författare)
- Karolinska Institutet,Department of Women’s and Children’s Health, Karolinska Institute, Stockholm, Sweden
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(creator_code:org_t)
- 2021-09-25
- 2021
- Engelska.
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Ingår i: Cell Death and Disease. - : Springer Nature. - 2041-4889. ; 12:10
- Relaterad länk:
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https://liu.diva-por... (primary) (Raw object)
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https://www.nature.c...
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https://doi.org/10.1...
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https://umu.diva-por... (primary) (Raw object)
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https://urn.kb.se/re...
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https://doi.org/10.1...
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http://kipublication...
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https://urn.kb.se/re...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Hematologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Hematology (hsv//eng)
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Cancer och onkologi (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Cancer and Oncology (hsv//eng)
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Malyukova, Alena
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Ujvari, Dorina
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Yektaei-Karin, E ...
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Zovko, Ana
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Madapura, Harsha ...
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Keszei, Marton
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visa fler...
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Nagy, Noemi
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Lotfi, Kourosh, ...
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Björn, Niclas
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Wallvik, Jonas
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Tamai, Minori
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Nguyen, Thao T. ...
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Akahane, Koshi
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Inukai, Takeshi
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Stenke, Leif
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Salamon, Daniel
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visa färre...
- Om ämnet
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Medicinsk biotek ...
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och Medicinsk biotek ...
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Hematologi
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- MEDICIN OCH HÄLSOVETENSKAP
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MEDICIN OCH HÄLS ...
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och Klinisk medicin
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och Cancer och onkol ...
- Artiklar i publikationen
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Cell Death and D ...
- Av lärosätet
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Linköpings universitet
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Karolinska Institutet
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Umeå universitet