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• W2984906187 abstract "Background: Whole-genome sequencing and expression studies have revealed significant heterogeneity in the molecular abnormalities driving AML. Selective inhibitors have been developed for many of the pathways influenced by these genetic alterations, but successful translation of these agents into the clinic is limited by both disease heterogeneity and drug resistance. Targeting of inflammatory pathways to block leukemia progression and eliminate leukemic clones is an emerging concept in AML therapy. We have shown that elevated levels of pro-inflammatory cytokine, interleukin-1 (IL-1), in AML microenvironment enhances the growth of leukemic progenitors in variety of genetic subtypes while inhibiting the normal progenitors' growth. To reveal molecular mechanisms underlying such paradoxical effect, we performed RNA-seq analysis on AML and healthy progenitors post IL-1 stimulation. We found myristoylated alanine-rich C-kinase substrate (MARCKS) is one of the most differentially expressed genes in AML progenitors compared to healthy progenitors. MARCKS is a major substrate of protein kinase C, and plays a crucial role in cell survival, migration, and cell cycle progression. Increased MARCKS expression promotes metastasis in solid tumors and inhibiting its activation is being proposed as a therapeutic strategy. However, its role in AML has not yet been investigated. Here, we show a crucial role of MARCKS activation in IL-1-mediated leukemia progression. Method and Results: Using the RNA-seq gene expression data of 451 primary AML patient samples (Tyner et al., Nature 2018), we tested the correlation of MARCKS with IL1R1 receptor expression in AML primary samples and found it to be positively correlated (r = 0.45, p < 0.0001). The correlation was regardless of sex, age, and mutation status. Using q-PCR and western blot analysis, we showed that MARCKS expression, protein level, and its activation (phosphorylation) are elevated in AML samples at basal level and after IL-1 stimulation when compared to the healthy progenitors (~3 fold change). These results validated our transcriptome data and suggested an important role for MARCKS in IL-1-mediated AML progression. To identify the functional significance of MARCKS in AML, we used two independent doxycycline inducible shRNAs to knockdown MARCKS in AML cell lines (MOLM-14 and THP-1). Our data show that MARCKS depletion in AML cells reduces the cell viability overtime to 40%, cell growth to 4 fold, and colony formation ability to 2 fold. Mechanistically, the knockdown of MARCKS in AML cells decreased SKP2 and increased p27 protein levels, suggesting MARCKS regulates cell cycle progression in these cells. We xenografted MOLM-14 cells expressing MARCKS shRNA into NSG mice by tail vein injections and induced the knockdown in vivo by feeding mice doxycycline containing chow. The bone marrow and spleen cells were analyzed by flow cytometry for human and mouse cell markers approximately 3 weeks post-treatment. We observed that the knockdown of MARCKS decreased the leukemia burden in xenograft model as observed by ~80% reduction in human leukemia cells in the bone marrow, ~40% reduction in human leukemia cells in spleen, and ~50% reduction in spleen size compared to the controls, suggesting MARCKS has a critical role in leukemia progression. Conclusion: MARCKS is over-expressed and -activated in various AML genetic subtypes. IL-1 stimulation of AML progenitors increases MARCKS phosphorylation. MARCKS promotes AML progression by increasing the cellular growth, survival, and cell cycle progression of leukemic cells. These results suggest that MARCKS may serve as marker for IL-1 mediated inflammatory stress and offers a route for new targeted therapy. Disclosures No relevant conflicts of interest to declare." @default.
• W2984906187 created "2019-11-22" @default.
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• W2984906187 date "2019-11-13" @default.
• W2984906187 modified "2023-10-18" @default.
• W2984906187 title "Marcks Is a Critical Downstream Mediator of IL-1-Driven AML Progression" @default.
• W2984906187 doi "https://doi.org/10.1182/blood-2019-129427" @default.
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