Reference - Detail
| 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 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 7 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Mice | RBRC01361 |