Session: 602. Disordered Gene Expression in Hematologic Malignancy, including Disordered Epigenetic Regulation: Poster III
Hematology Disease Topics & Pathways:
Biological Processes, epigenetics, immune mechanism, pathways
Aim: Our goal is to understand how loss of KDM6A affects gene transcription networks and enhancer function to affect MM pathogenesis or progression.
Method: We explored the transcriptional consequences of KDM6A deficiency in patient tumors using the gene expression dataset included within the Multiple Myeloma Research Foundation (MMRF) Researcher Gateway and in MM cell lines using data from the Cancer Cell Line Encyclopedia (CCLE). We further modeled the loss of KDM6A in female MM cell lines using CRISPR-Cas9 ribonucleotide protein (RNP) technology and by re-expressing KDM6A in cells null for KDM6A. Using ChIP-sequencing analysis in isogenic KDM6A knockout or replete cell lines, we identified KDM6A binding site in MM and explored how KDM6A deficiency affects chromatin structure to regulate a transcriptional network.
Results: Epithelial-to-mesenchymal-transition (EMT)-related pathways were downregulated in low KDM6A expressing tumor from the MMRF patient cohort. In both male and female patients, low expression of KDM6A was associated with decreased expression of genes involved in immune recognition. In MM cell lines, we observed a significant positive correlation between KDM6A expression level and expression of the transcriptional regulators of Major Histocompatibility complex I and II (MHCII and MCHII), NLRC5 and CIITA, respectively. With ChIP-sequencing analysis we find that KDM6A directly binds NLRC5 and CIITA genes, among many other genes involved in immune surveillance. KDM6A null MM cells displayed upregulation of pathways promoting EMT and downregulation of genes regulating immune function, such as HLA-A/B/C, CCL3/5, HHLA2 and ITGAL. Moreover, re-expression of KDM6A in KDM6A null cells upregulated the expression of these gene along with surface expression of MHCI proteins.
Conclusion: Together, our data demonstrates that KDM6A modulates EMT and directly regulates expression of major regulators of immune surveillance. KDM6A deficiency may drive MM towards an EMT program to promote systemic spread and facilitate escape from the immune surveillance.
Disclosures: No relevant conflicts of interest to declare.
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