CRISPR-Cas9 Library Screening Identifies Novel Molecular Vulnerabilities in KMT2A -Rearranged Acute Lymphoblastic Leukemia.

In acute lymphoblastic leukemia (ALL), chromosomal translocations involving the gene represent highly unfavorable prognostic factors and most commonly occur in patients less than 1 year of age. Rearrangements of the gene drive epigenetic changes that lead to aberrant gene expression profiles that strongly favor leukemia development. Apart from this genetic lesion, the mutational landscape of -rearranged ALL is remarkably silent, providing limited insights for the development of targeted therapy. Consequently, identifying potential therapeutic targets often relies on differential gene expression, yet the inhibition of these genes has rarely translated into successful therapeutic strategies. Therefore, we performed CRISPR-Cas9 knock-out screens to search for genetic dependencies in -rearranged ALL. We utilized small-guide RNA libraries directed against the entire human epigenome and kinome in various -rearranged ALL, as well as wild-type ALL cell line models. This screening approach led to the discovery of the epigenetic regulators and , as well as the receptor kinase as novel molecular vulnerabilities and attractive therapeutic targets in -rearranged ALL.