Automated CUT&Tag profiling of chromatin heterogeneity in mixed-lineage leukemia
Derek H Janssens 1, Michael P Meers 1, Steven J Wu 1 2, Ekaterina Babaeva 1, Soheil Meshinchi 3 4, Jay F Sarthy 1 4, Kami Ahmad 1, Steven Henikoff 5 6
Acute myeloid and lymphoid leukemias frequently harbor genetic translocations relating to the KMT2A gene, encoding the KMT2A lysine methyltransferase (also referred to as mixed-lineage leukemia-1), and convey in-frame fusions of KMT2A with other chromatin-regulatory proteins. Ideas map fusion-specific targets over the genome for diverse KMT2A oncofusion proteins in cell lines and patient samples. By modifying CUT&Tag chromatin profiling for full automation, we identify common and tumor-subtype-specific sites of aberrant chromatin regulation caused by KMT2A oncofusion proteins. A subset of KMT2A oncofusion-binding sites are marked by bivalent (H3K4me3 and H3K27me3) chromatin signatures, and single-cell CUT&Tag profiling reveals these sites display cell-to-cell heterogeneity an indication of lineage plasticity. Additionally, we discover that aberrant enrichment of H3K4me3 in gene physiques is responsive to Menin inhibitors, demonstrating the utility of automated chromatin profiling for identifying therapeutic vulnerabilities. Thus, integration of automated and single-cell CUT&Tag can uncover epigenomic heterogeneity within patient samples and predict sensitivity to therapeutic agents.VTP50469

Leave a Reply

Your email address will not be published. Required fields are marked *


You may use these HTML tags and attributes: <a href="" title=""> <abbr title=""> <acronym title=""> <b> <blockquote cite=""> <cite> <code> <del datetime=""> <em> <i> <q cite=""> <strike> <strong>