RNA terminal uridylyl transferases are druggable vulnerabilities in AML but are dispensable for normal hematopoiesis.

Authors

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

Published in

Science advances. Volume 12. Issue 33. Pages eaec3399. Aug 14, 2026. Epub Aug 12, 2026.

Abstract

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.

PMID:
42585304
Bibliographic data and abstract were imported from PubMed on 13 Aug 2026.

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