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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 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) as novel druggable therapeutic targets, whose genetic deletion in AML suppresses growth, induces apoptosis and improves the survival of leukemic mice. Notably, a pre-clinical TUT4/7 inhibitor promotes cell death in AML patient samples and synergizes with Venetoclax. Mechanistically, TUT4/7 inactivation disrupts cellular metabolism and suppresses mevalonate pathway gene expression, compromising the prenylation and cholesterol synthesis pathways. 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 lifespan and Tut4/7-deficiency does not compromise HSPC function. Thus, we reveal TUT4/7 as druggable targets, whose inactivation suppresses AML while sparing normal hematopoiesis. In combination with Venetoclax this represents a novel and promising therapeutic strategy.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Graeme Benstead-Hume

LAB HEAD: Jyoti Choudhary

PROVIDER: PXD077084 | Pride | 2026-06-24

REPOSITORIES: Pride

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	iLab359-CM-Kranc_15JAN26.msf	Msf
	iLab359-CM-Kranc_15JAN26.msfView	Msf
	iLab359-CM-Kranc_15JAN26.pdResult	Other

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

Project description: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 pre-clinical TUT4/7 inhibitor promotes cell death in AML patient samples 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 lifespan 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.

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