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

ABSTRACT: Acute myeloid leukemia (AML) is an aggressive hematological malignancy arising from blood-forming hematopoietic stem and progenitor cells (HSPCs). 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. Thus, we reveal TUT4/7 as novel druggable therapeutic targets, whose inactivation compromises AML while sparing normal hematopoiesis.

ORGANISM(S): Mus musculus

PROVIDER: GSE311841 | GEO | 2026/07/17

REPOSITORIES: GEO