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Survival outcomes have remained static in recent decades despite treatment intensification and novel therapies are urgently required. <jats:italic>KMT2A<\/jats:italic>-rearranged infant ALL cells are characterized by an abundance of promoter hypermethylation and exhibit high BCL-2 expression, highlighting potential for therapeutic targeting. Here, we show that hypomethylating agents exhibit in vitro additivity when combined with most conventional chemotherapeutic agents. However, in a subset of samples an antagonistic effect was seen between several agents. This was most evident when hypomethylating agents were combined with methotrexate, with upregulation of ATP-binding cassette transporters identified as a potential mechanism. Single agent treatment with azacitidine and decitabine significantly prolonged in vivo survival in <jats:italic>KMT2A<\/jats:italic>-rearranged infant ALL xenografts. Treatment of <jats:italic>KMT2A<\/jats:italic>-rearranged infant ALL cell lines with azacitidine and decitabine led to differential genome-wide DNA methylation, changes in gene expression and thermal proteome profiling revealed the target protein-binding landscape of these agents. The selective BCL-2 inhibitor, venetoclax, exhibited in vitro additivity in combination with hypomethylating or conventional chemotherapeutic agents. The addition of venetoclax to azacitidine resulted in a significant in vivo survival advantage indicating the therapeutic potential of this combination to improve outcome for infants with <jats:italic>KMT2A<\/jats:italic>-rearranged ALL.<\/jats:p>","DOI":"10.1038\/s41375-022-01746-3","type":"journal-article","created":{"date-parts":[[2022,11,15]],"date-time":"2022-11-15T09:02:42Z","timestamp":1668502962000},"page":"61-71","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Preclinical efficacy of azacitidine and venetoclax for infant KMT2A-rearranged acute lymphoblastic leukemia reveals a new therapeutic strategy"],"prefix":"10.1038","volume":"37","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6298-5288","authenticated-orcid":false,"given":"Laurence 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