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Abstract
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.
Highlights
Acute myeloid and lymphoid leukemias often harbor chromosomal translocations involving the KMT2A gene, encoding the KMT2A lysine methyltransferase, and produce in-frame fusions of KMT2A to other chromatin-regulatory proteins
This collection spans the spectrum of KMT2Ar leukemia subtypes with diverse KMT2A translocations that create oncogenic fusion proteins with the transcriptional elongation factors AF4 (SEM, RS4;11, 1° acute lymphoid leukemia (ALL)-1, 1° mixed-phenotype acute leukemia (MPAL)-2), AF9 (1° acute myeloid leukemia (AML)-3, 1° MPAL-1), 1Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 2Molecular Engineering and Sciences Institute, University of Washington, Seattle, WA, USA. 3Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. 4Cancer and Blood Disorder Center, Seattle Children’s Hospital, Seattle, WA, USA. 5Howard Hughes Medical Institute, Chevy Chase, MD, USA. ✉e-mail: steveh@fredhutch.org
DOT1L has been proposed to be a central component of oncogenic transformation by KMT2A fusion proteins in certain leukemias[14,42], and we found that the DOT1L histone methyltransferase was significantly more enriched at oncofusion protein targets in KOPN-8, 1° AML-3 and 1° MPAL-1 samples than in the other leukemias we profiled (Fig. 4b)
Summary
ENL (KOPN-8, 1° AML-2), AF6 (ML-2) and AF10 (1° AML-4, 1° AML-5) as well as a relatively rare fusion to the cytoplasmic GTPase SEPT6 (1° AML-1) (Supplementary Table 1). In the control H1 human embryonic stem cell line, only 15 of 17,000 KMT2A peaks were called as wide and these peaks were significantly less enriched on gene TSSs than the wide KMT2A peaks we identified in CD34+ HSPCs and significantly less enriched in gene bodies than the oncoprotein-binding sites in KMT2Ar leukemia samples (Fig. 1e and Extended Data Fig. 2m) This pattern of KMT2A fusion oncoproteins spreading across target gene bodies is consistent with previous reports[23,24]. Cells taken from the same leukemia sample and profiled in different experiments were clustered together in UMAP space, indicating that the data
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