# Targeting IMPDH to inhibit SAMHD1 in KMT2A-rearranged leukaemia

## TL;DR

This study explores how inhibiting IMPDH can improve the effectiveness of leukemia drugs by targeting SAMHD1, potentially offering new treatment options for some AML patients.

## Contribution

The study reveals that IMPDH inhibition synergizes with standard leukemia drugs in a SAMHD1-dependent manner, offering a novel therapeutic strategy.

## Key findings

- IMPDH inhibitors synergized with ara-C and F-ara-A in a subset of AML cells, but not in ALL cells.
- IMPDH inhibition depleted GTP and dGTP, increasing active triphosphate metabolites in SAMHD1-proficient cells.
- Sensitivity to IMPDH inhibitors was independent of KMT2A status in AML cells.

## 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.