SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism
Autor: | Michal Mikula, Katarzyna Piwocka, Jolanta Wozniak, Ewa Jabłońska, Elżbieta Patkowska, Eliza Glodkowska-Mrowka, Patryk Górniak, Agnieszka Kolkowska-Lesniak, Przemyslaw Juszczynski, Natalia Baran, Marta Stojak, Karolina Piechna, Ewa Lech-Marańda, Beata Krzymieniewska, Lukasz Bugajski, Monika Noyszewska-Kania, Maciej Szydlowski, Anna Polak, Ewelina Kaniuga, Emilia Bialopiotrowicz, Magdalena Cybulska, Joanna Barankiewicz |
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Jazyk: | angličtina |
Rok vydání: | 2020 |
Předmět: |
Cancer Research
Cell Respiration Immunology Syk Apoptosis Mice SCID Fostamatinib Oxidative Phosphorylation Article Mice Cellular and Molecular Neuroscience Mice Inbred NOD hemic and lymphatic diseases STAT5 Transcription Factor Tumor Cells Cultured medicine Animals Humans Syk Kinase lcsh:QH573-671 Protein Kinase Inhibitors Oncogenesis STAT5 Cell Proliferation biology Gene Expression Regulation Leukemic Cancer stem cells Kinase Chemistry lcsh:Cytology Tumor Suppressor Proteins Myeloid leukemia hemic and immune systems Cell Biology Translational research medicine.disease Xenograft Model Antitumor Assays Leukemia Myeloid Acute Oxidative Stress Leukemia Mitochondrial biogenesis Neoplastic Stem Cells Cancer research biology.protein Female Stem cell medicine.drug |
Zdroj: | Cell Death and Disease, Vol 11, Iss 11, Pp 1-15 (2020) Cell Death & Disease |
ISSN: | 2041-4889 |
Popis: | Spleen tyrosine kinase (SYK) is an important oncogene and signaling mediator activated by cell surface receptors crucial for acute myeloid leukemia (AML) maintenance and progression. Genetic or pharmacologic inhibition of SYK in AML cells leads to increased differentiation, reduced proliferation, and cellular apoptosis. Herein, we addressed the consequences of SYK inhibition to leukemia stem-cell (LSC) function and assessed SYK-associated pathways in AML cell biology. Using gain-of-function MEK kinase mutant and constitutively active STAT5A, we demonstrate that R406, the active metabolite of a small-molecule SYK inhibitor fostamatinib, induces differentiation and blocks clonogenic potential of AML cells through the MEK/ERK1/2 pathway and STAT5A transcription factor, respectively. Pharmacological inhibition of SYK with R406 reduced LSC compartment defined as CD34+CD38−CD123+ and CD34+CD38−CD25+ in vitro, and decreased viability of LSCs identified by a low abundance of reactive oxygen species. Primary leukemic blasts treated ex vivo with R406 exhibited lower engraftment potential when xenotransplanted to immunodeficient NSG/J mice. Mechanistically, these effects are mediated by disturbed mitochondrial biogenesis and suppression of oxidative metabolism (OXPHOS) in LSCs. These mechanisms appear to be partially dependent on inhibition of STAT5 and its target gene MYC, a well-defined inducer of mitochondrial biogenesis. In addition, inhibition of SYK increases the sensitivity of LSCs to cytarabine (AraC), a standard of AML induction therapy. Taken together, our findings indicate that SYK fosters OXPHOS and participates in metabolic reprogramming of AML LSCs in a mechanism that at least partially involves STAT5, and that SYK inhibition targets LSCs in AML. Since active SYK is expressed in a majority of AML patients and confers inferior prognosis, the combination of SYK inhibitors with standard chemotherapeutics such as AraC constitutes a new therapeutic modality that should be evaluated in future clinical trials. |
Databáze: | OpenAIRE |
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