Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition
Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a dismal prognosis. The cytoplasmic spleen tyrosine kinase (SYK) is highly expressed by hematopoietic cells and has emerged as a potential therapeutic target. In this study, we evaluated the in vitro antileukemic effects of...
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MDPI AG
2022-11-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/23/14706 |
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| author | Marte Karen Brattås Anette Lodvir Hemsing Kristin Paulsen Rye Kimberley Joanne Hatfield Håkon Reikvam |
| author_facet | Marte Karen Brattås Anette Lodvir Hemsing Kristin Paulsen Rye Kimberley Joanne Hatfield Håkon Reikvam |
| author_sort | Marte Karen Brattås |
| collection | DOAJ |
| description | Acute myeloid leukemia (AML) is an aggressive hematological malignancy with a dismal prognosis. The cytoplasmic spleen tyrosine kinase (SYK) is highly expressed by hematopoietic cells and has emerged as a potential therapeutic target. In this study, we evaluated the in vitro antileukemic effects of five SYK inhibitors, fostamatinib, entospletinib, cerdulatinib, TAK-659, and RO9021, in a consecutive AML patient cohort. All inhibitors demonstrated a concentration-dependent antiproliferative effect, although there was considerable heterogeneity among patients. For fostamatinib and TAK-659, the antiproliferative effects were significantly higher in <i>FLT3</i> mutated patients compared to nonmutated patients. Fostamatinib, entospletinib, TAK-659, and RO9021 induced significant apoptosis in primary AML cells, although the proapoptotic effects of the SYK inhibitors were less pronounced than the antiproliferative effects. Finally, most of the SYK inhibitors caused a significant decrease in the release of cytokines and chemokines from primary AML cells, indicating a potent inhibitory effect on the release of these leukemic signaling molecules. We concluded that the SYK inhibitors had antileukemic effects in AML, although larger studies are strongly needed to identify which patient subsets will benefit most from such a treatment. |
| first_indexed | 2024-03-09T17:46:27Z |
| format | Article |
| id | doaj.art-61ff0414e7cd45368e754fe315b38c46 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T17:46:27Z |
| publishDate | 2022-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-61ff0414e7cd45368e754fe315b38c462023-11-24T11:06:30ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-11-0123231470610.3390/ijms232314706Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro InhibitionMarte Karen Brattås0Anette Lodvir Hemsing1Kristin Paulsen Rye2Kimberley Joanne Hatfield3Håkon Reikvam4Department of Clinical Science, University of Bergen, 5021 Bergen, NorwayDepartment of Clinical Science, University of Bergen, 5021 Bergen, NorwayDepartment of Clinical Science, University of Bergen, 5021 Bergen, NorwayDepartment of Immunology and Transfusion Medicine, Haukeland University Hospital, 5021 Bergen, NorwayDepartment of Clinical Science, University of Bergen, 5021 Bergen, NorwayAcute myeloid leukemia (AML) is an aggressive hematological malignancy with a dismal prognosis. The cytoplasmic spleen tyrosine kinase (SYK) is highly expressed by hematopoietic cells and has emerged as a potential therapeutic target. In this study, we evaluated the in vitro antileukemic effects of five SYK inhibitors, fostamatinib, entospletinib, cerdulatinib, TAK-659, and RO9021, in a consecutive AML patient cohort. All inhibitors demonstrated a concentration-dependent antiproliferative effect, although there was considerable heterogeneity among patients. For fostamatinib and TAK-659, the antiproliferative effects were significantly higher in <i>FLT3</i> mutated patients compared to nonmutated patients. Fostamatinib, entospletinib, TAK-659, and RO9021 induced significant apoptosis in primary AML cells, although the proapoptotic effects of the SYK inhibitors were less pronounced than the antiproliferative effects. Finally, most of the SYK inhibitors caused a significant decrease in the release of cytokines and chemokines from primary AML cells, indicating a potent inhibitory effect on the release of these leukemic signaling molecules. We concluded that the SYK inhibitors had antileukemic effects in AML, although larger studies are strongly needed to identify which patient subsets will benefit most from such a treatment.https://www.mdpi.com/1422-0067/23/23/14706acute myeloid leukemia (AML)apoptosiscytokinesproliferationspleen tyrosine kinase (SYK) |
| spellingShingle | Marte Karen Brattås Anette Lodvir Hemsing Kristin Paulsen Rye Kimberley Joanne Hatfield Håkon Reikvam Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition International Journal of Molecular Sciences acute myeloid leukemia (AML) apoptosis cytokines proliferation spleen tyrosine kinase (SYK) |
| title | Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition |
| title_full | Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition |
| title_fullStr | Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition |
| title_full_unstemmed | Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition |
| title_short | Heterogeneity of Patient-Derived Acute Myeloid Leukemia Cells Subjected to SYK In Vitro Inhibition |
| title_sort | heterogeneity of patient derived acute myeloid leukemia cells subjected to syk in vitro inhibition |
| topic | acute myeloid leukemia (AML) apoptosis cytokines proliferation spleen tyrosine kinase (SYK) |
| url | https://www.mdpi.com/1422-0067/23/23/14706 |
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