RNA terminal uridylyl transferases are druggable vulnerabilities in AML but are dispensable for normal hematopoiesis
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Christopher Mapperley Elise Georges Ali A Azar Yuka Kabayama Hannah Lawson Iwo Kucinski Derek George Joana Campos Corey Fyfe Jozef Durko Wei Chan Lewis Allen Babak Jazayeri Edward Blacker Louie N van de Lagemaat Aurelien Tripp Theodoros I Roumeliotis Giulia Guiducci Ellie Herbert Jasmin Paris Jyoti Choudhary George Poulogiannis Robert M Campbell Marcos Morgan Lovorka Stojic Folkert Van Werven Douglas Vernimmen Berthold Göttgens Dónal O'Carroll Kamil R Kranc
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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.
Journal details
Journal
Science advances
Volume
12
Issue number
33
Pages
eaec3399
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10.1126/sciadv.aec3399
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Europe PubMed Central
42585304
Pubmed
42585304
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