Repurposing immunosuppressants for antileukemia therapy

Abstract

Drug repurposing, the strategy to identify new therapeutic use for clinically approved drugs has attracted much attention in recent years. This strategy offers various advantages over traditional approaches to develop new drugs, including shorter development timelines, low cost, and reduced risk of failure. In this issue of EMBO Molecular Medicine, Liu et al show that inosine monophosphate dehydrogenase (IMPDH) inhibitors, the well-known immunosuppressants have a potent therapeutic effect on the aggressive blood cancer, acute myeloid leukemia with MLL rearrangements. Intriguingly, the antileukemia effect of IMPDH inhibitors is mediated, at least in part through the overactivation of TLR signaling and Vcam1 upregulation. The robust antileukemia effect of IMPDH inhibitors, both in vitro and in vivo, together with their mechanistic findings provides a rational basis for repurposing IMPDH inhibitors for antileukemia therapy.

Figure 1. The diverse effects of IMPDH inhibitors in MLL‐rearranged AML

IMPDH is a rate‐limiting enzyme in the de novo GTP synthesis pathway that catalyzes the conversion of IMP to XMP. MPA and FF‐10501‐01 are IMPDH inhibitors used in this study. In addition to the reduction of guanine nucleotides (GMP, GDP, and GTP), IMPDH inhibition induces diverse metabolic and epigenetic changes in MLL‐rearranged AML cells, such as downregulation of CD98/Lat1 and mTORC1 signaling, activation of p53‐p21 pathway, activation of TLR‐NF‐κβ signaling, and Vcam1 upregulation. EAAs, essential amino acids; IMPDH, inosine monophosphate dehydrogenase.