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Here we map fusion-specific targets across the genome for diverse KMT2A oncofusion proteins in cell lines and patient samples. By modifying CUT&amp;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&amp;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&amp;Tag can uncover epigenomic heterogeneity within patient samples and predict sensitivity to therapeutic agents.\n                  <\/jats:p>","DOI":"10.1038\/s41588-021-00941-9","type":"journal-article","created":{"date-parts":[[2021,10,18]],"date-time":"2021-10-18T20:13:50Z","timestamp":1634588030000},"page":"1586-1596","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":94,"title":["Automated CUT&amp;Tag profiling of chromatin heterogeneity in mixed-lineage leukemia"],"prefix":"10.1038","volume":"53","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1079-9525","authenticated-orcid":false,"given":"Derek H.","family":"Janssens","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3438-3938","authenticated-orcid":false,"given":"Michael P.","family":"Meers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven J.","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ekaterina","family":"Babaeva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Soheil","family":"Meshinchi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5244-7865","authenticated-orcid":false,"given":"Jay F.","family":"Sarthy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kami","family":"Ahmad","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7621-8685","authenticated-orcid":false,"given":"Steven","family":"Henikoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,18]]},"reference":[{"key":"941_CR1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.3389\/fped.2017.00004","volume":"5","author":"AC Winters","year":"2017","unstructured":"Winters, A. C. & Bernt, K. M. MLL-rearranged leukemias\u2014an update on science and clinical approaches. Front. Pediatr. 5, 4 (2017).","journal-title":"Front. Pediatr."},{"key":"941_CR2","doi-asserted-by":"crossref","first-page":"194579","DOI":"10.1016\/j.bbagrm.2020.194579","volume":"1863","author":"ETB Antunes","year":"2020","unstructured":"Antunes, E. T. B. & Ottersbach, K. The MLL\/SET family and haematopoiesis. Biochim. Biophys. Acta Gene Regul. Mech. 1863, 194579 (2020).","journal-title":"Biochim. Biophys. Acta Gene Regul. Mech."},{"key":"941_CR3","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.cell.2005.04.031","volume":"121","author":"Y Dou","year":"2005","unstructured":"Dou, Y. et al. Physical association and coordinate function of the H3 K4 methyltransferase MLL1 and the H4 K16 acetyltransferase MOF. 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J., Ernst, P., Erdjument-Bromage, H., Tempst, P. & Korsmeyer, S. J. Proteolytic cleavage of MLL generates a complex of N- and C-terminal fragments that confers protein stability and subnuclear localization. Mol. Cell. Biol. 23, 186\u2013194 (2003).","journal-title":"Mol. Cell. Biol."},{"key":"941_CR9","doi-asserted-by":"crossref","first-page":"5215","DOI":"10.1038\/onc.2016.30","volume":"35","author":"RK Slany","year":"2016","unstructured":"Slany, R. K. The molecular mechanics of mixed lineage leukemia. Oncogene 35, 5215\u20135223 (2016).","journal-title":"Oncogene"},{"key":"941_CR10","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1101\/gad.284109.116","volume":"30","author":"D Hu","year":"2016","unstructured":"Hu, D. & Shilatifard, A. Epigenetics of hematopoiesis and hematological malignancies. 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