RNA Terminal Uridylyl-Transferases Are Druggable Vulnerabilities in AML, but are Dispensable for Normal Hematopoiesis

Current therapies often fail to eradicate AML, therefore, identification of novel therapeutic targets is essential. Here, we reveal Terminal Uridylyl Transferase Enzymes 4 and 7 (TUT4/7) as druggable novel therapeutic targets whose genetic deletion in AML suppresses growth, induces apoptosis and improves the survival of in vivo mouse models.

Use of a pre-clinical TUT4/7 inhibitor is cytotoxic to AML patient samples, dysregulates mevalonate pathway genes and synergizes with Venetoclax. AML therapies are often limited by hematopoietic toxicity. Remarkably, we find that although Tut4/7 deletion results in mild inflammatory activation throughout the hematopoietic system, this activation is largely permissive, and mice exhibit no overt pathology for at least one year.