RRC ID 76654
Author Liu X, Sato N, Yabushita T, Li J, Jia Y, Tamura M, Asada S, Fujino T, Fukushima T, Yonezawa T, Tanaka Y, Fukuyama T, Tsuchiya A, Shikata S, Iwamura H, Kinouchi C, Komatsu K, Yamasaki S, Shibata T, Sasaki AT, Schibler J, Wunderlich M, O'Brien E, Mizukawa B, Mulloy JC, Sugiura Y, Takizawa H, Shibata T, Miyake K, Kitamura T, Goyama S.
Title IMPDH inhibition activates TLR-VCAM1 pathway and suppresses the development of MLL-fusion leukemia.
Journal EMBO Mol Med
Abstract Inosine monophosphate dehydrogenase (IMPDH) is a rate-limiting enzyme in de novo guanine nucleotide synthesis pathway. Although IMPDH inhibitors are widely used as effective immunosuppressants, their antitumor effects have not been proven in the clinical setting. Here, we found that acute myeloid leukemias (AMLs) with MLL-fusions are susceptible to IMPDH inhibitors in vitro. We also showed that alternate-day administration of IMPDH inhibitors suppressed the development of MLL-AF9-driven AML in vivo without having a devastating effect on immune function. Mechanistically, IMPDH inhibition induced overactivation of Toll-like receptor (TLR)-TRAF6-NF-κB signaling and upregulation of an adhesion molecule VCAM1, which contribute to the antileukemia effect of IMPDH inhibitors. Consequently, combined treatment with IMPDH inhibitors and the TLR1/2 agonist effectively inhibited the development of MLL-fusion AML. These findings provide a rational basis for clinical testing of IMPDH inhibitors against MLL-fusion AMLs and potentially other aggressive tumors with active TLR signaling.
Volume 15(1)
Pages e15631
Published 2023-1-11
DOI 10.15252/emmm.202115631
PMID 36453131
PMC PMC9832838
MeSH Enzyme Inhibitors / pharmacology Humans Immunosuppressive Agents / therapeutic use Leukemia, Myeloid, Acute* / drug therapy Leukemia, Myeloid, Acute* / pathology Myeloid-Lymphoid Leukemia Protein* / metabolism NF-kappa B
IF 8.821
Mice RBRC01361