2. Academic Validation
  3. Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia

Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia

  • Cell Cycle. 2025 Dec 15:1-19. doi: 10.1080/15384101.2025.2601796.
Yolande Klootsema 1,  Nikolaos Tsesmetzis 1,  Sushma Sharma 2,  Sophia Hofmann 3,  Jonas Thier 3,  Christopher Dirks 4,  Femke M Hormann 4,  Miriam Yagüe-Capilla 4 5 6,  Anna Bohlin 3 7,  Sofia Bengtzen 3 7,  Sören Lehmann 7 8 9,  Andrei Chabes 2,  Martin Jädersten 3 7,  Vanessa Lundin 3,  Sean G Rudd 4,  Ingrid Lilienthal 1,  Nikolas Herold 1 10
Affiliations

Affiliations

  • 1 Division of Paediatric Oncology and Surgery, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
  • 2 Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden.
  • 3 Center for Haematology and Regenerative Medicine, Department of Medicine Huddinge, Karolinska Institutet, Huddinge, Sweden.
  • 4 Science for Life Laboratory (SciLifeLab), Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
  • 5 Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain.
  • 6 Departamento de Biología Celular, Facultad de Biología, Universidad de Sevilla, Sevilla, Spain.
  • 7 Department of Medicine, Division of Hematology, Karolinska University Hospital, Huddinge, Sweden.
  • 8 Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
  • 9 Hematology Unit, Department of Medical Sciences, Uppsala University, Uppsala, Sweden.
  • 10 Paediatric Oncology, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
PMID: 41399259 DOI: 10.1080/15384101.2025.2601796
Abstract

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.

Keywords

IMPDH; KMT2A; SAMHD1; leukemia; therapy resistance.

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