Automated CUT&Tag profiling of chromatin heterogeneity in mixed-lineage leukemia.

Autor: Janssens DH; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Meers MP; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Wu SJ; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.; Molecular Engineering and Sciences Institute, University of Washington, Seattle, WA, USA., Babaeva E; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Meshinchi S; Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.; Cancer and Blood Disorder Center, Seattle Children's Hospital, Seattle, WA, USA., Sarthy JF; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.; Cancer and Blood Disorder Center, Seattle Children's Hospital, Seattle, WA, USA., Ahmad K; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Henikoff S; Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. steveh@fredhutch.org.; Howard Hughes Medical Institute, Chevy Chase, MD, USA. steveh@fredhutch.org.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2021 Nov; Vol. 53 (11), pp. 1586-1596. Date of Electronic Publication: 2021 Oct 18.
DOI: 10.1038/s41588-021-00941-9
Abstrakt: Acute myeloid and lymphoid leukemias often harbor chromosomal translocations involving the KMT2A gene, encoding the KMT2A lysine methyltransferase (also known as mixed-lineage leukemia-1), and produce in-frame fusions of KMT2A to other chromatin-regulatory proteins. Here we map fusion-specific targets across 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 induced 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 that these sites display cell-to-cell heterogeneity suggestive of lineage plasticity. In addition, we find that aberrant enrichment of H3K4me3 in gene bodies is sensitive 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.
(© 2021. The Author(s).)
Databáze: MEDLINE
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