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Inhibition of Slug effectively targets leukemia stem cells via the Slc13a3/ROS signaling pathway.

ABSTRACT: Leukemia stem cells (LSCs) are the rare populations of acute myeloid leukemia (AML) cells that are able to initiate, maintain, and propagate AML. Targeting LSCs is a promising approach for preventing AML relapse and improving long-term outcomes. While Slug, a zinc-finger transcription repressor, negatively regulates the self-renewal of normal hematopoietic stem cells, its functions in AML are still unknown. We report here that Slug promotes leukemogenesis and its loss impairs LSC self-renewal and delays leukemia progression. Mechanistically, Slc13a3, a direct target of Slug in LSCs, restricts the self-renewal of LSCs and markedly prolongs recipient survival. Genetic or pharmacological inhibition of SLUG or forced expression of Slc13a3 suppresses the growth of human AML cells. In conclusion, our studies demonstrate that Slug differentially regulates self-renewal of LSCs and normal HSCs, and both Slug and Slc13a3 are potential therapeutic targets of LSCs.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC6995768 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Inhibition of Slug effectively targets leukemia stem cells via the Slc13a3/ROS signaling pathway.

Zhang Zhonghui Z Li Lei L Wu Chen C Yin Guoshu G Zhu Pei P Zhou Yalu Y Hong Yuanfan Y Ni Hongyu H Qian Zhijian Z Wu Wen-Shu WS

Leukemia 20190906 2

Leukemia stem cells (LSCs) are the rare populations of acute myeloid leukemia (AML) cells that are able to initiate, maintain, and propagate AML. Targeting LSCs is a promising approach for preventing AML relapse and improving long-term outcomes. While Slug, a zinc-finger transcription repressor, negatively regulates the self-renewal of normal hematopoietic stem cells, its functions in AML are still unknown. We report here that Slug promotes leukemogenesis and its loss impairs LSC self-renewal an ...[more]

PMID: 31492896

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Project description:ObjectiveThe escape from T cell-mediated immune surveillance is an important cause of death for patients with acute myeloid leukemia (AML). This study aims to identify clonal heterogeneity in leukemia progenitor cells and explore molecular or signaling pathways associated with AML immune escape.MethodsSingle-cell RNA sequencing (scRNA-seq) was performed to identified AML-related cellular subsets, and intercellular communication was analyzed to investigate molecular mechanisms associated with AML immune escape. Bulk RNA sequencing (RNA-seq) was performed to screen differentially expressed genes (DEGs) related to hematopoietic stem cell progenitors (HSC-Prog) in AML, and critical ore signaling pathways and hub genes were found by Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis. The mRNA level of the hub gene was verified using quantitative real-time PCR (qRT-PCR) and the protein level of human leukocyte antigen A (HLA-A) using enzyme-linked immuno sorbent assay (ELISA).ResultsscRNA-seq analysis revealed a large heterogeneity of HSC-Prog across samples, and the intercellular communication analysis indicated a strong association between HSC-Prog and CD8+-T cells, and HSC-Prog also had an association with HLA-A. Transcriptome analysis identified 1748 DEGs, enrichment analysis results showed that non-classical wnt signaling pathway was associated with AML, and 4 pathway-related genes (RHOA, RYK, CSNK1D, NLK) were obtained. After qRT-PCR and ELISA validation, hub genes and HLA-A were found to be down-regulated in AML and up-regulated after activation of the non-classical Wnt signaling pathway.ConclusionIn this study, clonal heterogeneity of HSC-Prog cells in AML was identified, non-classical wnt signaling pathways associated with AML were identified, and it was verified that HLA-A could be upregulated by activation of non-classical wnt signaling, thereby increasing antigen presentation.

Project description: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.

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Inhibition of Slug effectively targets leukemia stem cells via the Slc13a3/ROS signaling pathway.

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Inhibition of Slug effectively targets leukemia stem cells via the Slc13a3/ROS signaling pathway.

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