|  Help  |  About  |  Contact Us

Publication : IMPDH inhibition activates TLR-VCAM1 pathway and suppresses the development of MLL-fusion leukemia.

First Author  Liu X Year  2023
Journal  EMBO Mol Med Volume  15
Issue  1 Pages  e15631
PubMed ID  36453131 Mgi Jnum  J:346913
Mgi Id  MGI:7426385 Doi  10.15252/emmm.202115631
Citation  Liu X, et al. (2023) IMPDH inhibition activates TLR-VCAM1 pathway and suppresses the development of MLL-fusion leukemia. EMBO Mol Med 15(1):e15631
abstractText  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-kappaB 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.
Quick Links:
 
Quick Links:
 

Expression

Publication --> Expression annotations

 

Other

7 Bio Entities

Trail: Publication

0 Expression