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RNA-seq of murine spleocytes

ABSTRACT: Aberrant expression of the T-cell lymphoma/leukemia 1A (TCL1A) oncogene is a hallmark of chronic lymphocytic leukemia (CLL) and is associated with aggressive disease features. A better understanding of functional networks around TCL1A is required to develop new treatment approaches in CLL. Here, we identify the epigenetic modifying lysine-specific demethylase KDM1A as a nuclear interaction partner of the TCL1A protein in CLL B-cells. Interestingly, binding to TCL1A increased KDM1A?s demethylase activity. Moreover, higher KDM1A expression correlated with adverse clinical characteristics and shorter progression-free survival in CLL. Kdm1a knockdown (Kdm1a-KD) reduced leukemic burden and prolonged overall survival in a CLL mouse model accompanied by upregulation of p53 and pro-apoptotic pathways. RNA-seq analysis of differentially expressed genes upon Kdm1a-KD suggests that Kdm1a might act as a transcriptional repressor. In addition, ChIP experiments demonstrated an altered modification of H3K4me3 in Kdm1a-KD mice. Moreover, KDM1A expression in the microenvironmental had an impact on its support for CLL progression. In line, KDM1A inhibition by the pharmacologic compound C12 induced apoptosis and affected H3K4/9 target methylation levels in B-cell lines and CLL samples. Overall, we found a relevant pathogenetic role of KDM1A as a pro-oncogenic marker in CLL cells and their microenvironment. This provides a novel treatment rationale for targeting KDM1A in CLL.

ORGANISM(S): Mus musculus

PROVIDER: GSE190108 | GEO | 2023/05/02

REPOSITORIES: GEO

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Project description:Among all cancers, colorectal cancer (CRC) is the 3rd most common and the 2nd leading cause of death worldwide. New therapeutic strategies are required to target cancer stem cells (CSCs), a subset of tumor cells highly resistant to present-day therapy and responsible for tumor relapse. CSCs display dynamic genetic and epigenetic alterations that allow quick adaptations to perturbations. Lysine-specific histone demethylase 1A (KDM1A), a FAD-dependent H3K4me1/2 and H3K9me1/2 demethylase, was found to be upregulated in several tumors and associated with a poor prognosis due to its ability to maintain CSCs staminal features. Here, we explored the potential role of KDM1A targeting in CRC by characterizing the effect of KDM1A silencing in differentiated and CRC stem cells (CRC-SCs). In CRC primary samples, KDM1A expression was associated with a worse prognosis, confirming its role as an independent negative prognostic factor of CRC. Consistently, biological assays such as methylcellulose colony formation, invasion, and migration assays demonstrated a significantly decreased self-renewal potential, as well as migration and invasion potential upon KDM1A silencing. Our untargeted omics approach (transcriptomic and proteomic) revealed the association of KDM1A silencing with CRC-SCs cytoskeletal and metabolism remodeling towards a differentiated phenotype (e.g., the activation of a collateral mitochondrial metabolic pathway independent from succinate-CoA ligase GDP-forming subunit beta 2, expressions of brush border’s protein villin, and ketogenic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A synthase 2) suggesting a key role of KDM1A in cell metabolism. Also, KDM1A silencing resulted in a 3-fold increase in the expression of miR-506-3p. Lastly, loss of KDM1A markedly reduced 53BP1 DNA repair foci, implying the involvement of KDM1A in the DNA damage response. Overall, our results indicate that KDM1A plays a key role in CRC progression and therefore it represents a promising epigenetic target to prevent tumor relapse.

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RNA-seq of murine spleocytes

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