RNA terminal uridylyl transferases are druggable vulnerabilities in AML but are dispensable for normal hematopoiesis
- 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
2026-08-12
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.