Journal Article

SYK inhibition targets acute myeloid leukemia stem cells by blocking their oxidative metabolism

Szydlowski, Maciej, Stojak, Marta, Lech-Maranda, Ewa, Kolkowska-Lesniak, Agnieszka, Piwocka, Katarzyna, Krzymieniewska, Beata, Mikula, Michał, Noyszewska-Kania, Monika, Glodkowska-Mrowka, Eliza, Kaniuga, Ewelina, Wozniak, Jolanta, Bugajski, Lukasz, Barankiewicz, Joanna, Juszczynski, Przemyslaw, Jablonska, Ewa, Bialopiotrowicz, Emilia, Cybulska, Magdalena, Piechna, Karolina, Polak, Anna, Baran, Natalia, Gorniak, Patryk, Patkowska, Elzbieta

2020

Overview

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.

• Publisher: Nature Publishing Group UK,Springer Nature B.V
• Subject: 13/89 / 13/95 / 14/34 / 42/109 / 45/77 / 631/532/71 / 692/308/575 / 692/420/755 / 96/100 / 96/106 / 96/2 / 96/31 / 96/44 / Acute myeloid leukemia / Antibodies / Apoptosis / Biochemistry / Biomedical and Life Sciences / Biosynthesis / CD123 antigen / CD25 antigen / CD34 antigen / CD38 antigen / Cell Biology / Cell Culture / Cell differentiation / Cell proliferation / Cell surface / Chemotherapy / Clinical trials / Cytarabine / Extracellular signal-regulated kinase / Immunodeficiency / Immunology / Induction therapy / Kinases / Leukemia / Life Sciences / MEK kinase / Metabolism / Metabolites / Mitochondria / Myc protein / Myeloid leukemia / Oxidative metabolism / Protein-tyrosine kinase / Reactive oxygen species / Spleen / Stat5 protein / Stem cells / Xenografts