Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia [Dataset]

Cytarabine (ara-C) and fludarabine (F-ara-A) are key drugs in leukaemia treatment. SAMHD1 is known to confer resistance to ara-C and F-ara-A, and we previously identified ribonucleotide reductase inhibitors as indirect SAMHD1 inhibitors in a phenotypic screen. The inosine monophosphate dehydrogenase...

Descripción completa

Detalles Bibliográficos
Autores: Klootsema, Yolande, Tsesmetzis, Nikolaos, Sharma, Sushma, Hofmann, Sophia, Thier, Jonas, Dirks, Christopher, Hormann, Femke M., Yagüe-Capilla, Miriam, Bohlin, Anna, Bengtzen, Sofia, Lehmann, Sören, Chabes, Andrei, Jädersten, Martin, Lundin, Vanessa, Rudd, Sean G., Lilienthal, Ingrid, Herold, Nikolas
Tipo de recurso: conjunto de datos
Fecha de publicación:2026
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:dnet:digitalcsic_::e9bbca1e4a5ae7c1d8371cbc404921e6
Acceso en línea:http://hdl.handle.net/10261/427974
Access Level:acceso abierto
Palabra clave:IMPDH
KMT2A
Leukemia
SAMHD1
Therapy resistance
Biochemistry
Space sciences
Medicine
Cell biology
Human genetics
Molecular biology
Pharmacology
Ecology
Cancer
Descripción
Sumario:Cytarabine (ara-C) and fludarabine (F-ara-A) are key drugs in leukaemia treatment. SAMHD1 is known to confer resistance to ara-C and F-ara-A, and we previously identified ribonucleotide reductase inhibitors as indirect SAMHD1 inhibitors in a phenotypic screen. The inosine monophosphate dehydrogenase (IMPDH) inhibitor mycophenolic acid (MPA) was also a hit in this screen. IMPDH inhibitors (IMPDHi) have previously shown efficacy against KMT2A-rearranged (KMT2Ar) acute myeloid leukaemia (AML). We investigated whether IMPDH inhibition could enhance the effect of ara-C and F-ara-A in AML cell lines and primary AML samples, and whether this effect was linked to KMT2A status. We found that sensitivity to IMPDHi was independent of KMT2A status. IMPDHi synergized with ara-C and F-ara-A in a SAMHD1-dependent manner in a subset of AML cells, but not in acute lymphoblastic leukaemia cell lines. Mechanistically, IMPDHi depleted allosteric SAMHD1 activators GTP and dGTP, thereby increasing active triphosphate metabolites in SAMHD1-proficient, but not SAMHD1-deficient, cells. Our findings suggest that the addition of IMPDHi to ara-C and F-ara-A may have therapeutic benefits in some AML cases.

Similares en LA Referencia