Christopher Mapperley, Elise Georges, Ali A Azar, Yuka Kabayama, Hannah Lawson, Iwo Kucinski, Derek George, Joana Campos, Corey Fyfe, Jozef Durko, Wei Y Chan, Lewis Allen, Babak Jazayeri, Edward Blacker, Louie N van de Lagemaat, Aurelien Tripp, Theodoros I Roumeliotis, Giulia Guiducci, Eleanor Herbert, Jasmin Paris, Jyoti Choudhary, George Poulogiannis, Robert M Campbell, Marcos Morgan, Lovorka Stojic, Folkert J Van Werven, Douglas Vernimmen, Berthold Göttgens, Dónal O'Carroll, Kamil R Kranc
Acute myeloid leukemia (AML) is an aggressive hematological malignancy arising from hematopoietic stem and progenitor cells (HSPCs). Current treatments often fail to eradicate AML; therefore, new therapeutic strategies are essential. Here, we reveal that RNA terminal uridylyl transferase enzymes 4 and 7 (TUT4/7) are druggable therapeutic targets, whose genetic deletion suppresses AML growth, induces apoptosis, and improves the survival in leukemic mouse models. Notably, a preclinical TUT4/7 inhibitor promotes cell death in samples from patients with AML and synergizes with venetoclax. Mechanistically, TUT4/7 inactivation suppresses mevalonate pathway gene expression, compromising the cholesterol synthesis pathway. Current AML therapies often cause severe hematopoietic toxicity. Although Tut4/7 deletion results in inflammatory activation throughout the hematopoietic system, this is permissive to a normal life span and Tut4/7 deficiency does not compromise HSPC function. Together, these findings identify TUT4/7 as druggable targets, whose inactivation suppresses AML while sparing normal hematopoiesis. In combination with venetoclax, this represents a promising therapeutic strategy.