Journal Article

IMPDH inhibition activates TLR‐VCAM1 pathway and suppresses the development of MLL‐fusion leukemia

Yabushita, Tomohiro, Mulloy, James C, Kitamura, Toshio, Komatsu, Kensuke, Asada, Shuhei, Tanaka, Yosuke, Fukushima, Tsuyoshi, Shibata, Takuma, Goyama, Susumu, Wunderlich, Mark, Fujino, Takeshi, Mizukawa, Benjamin, Sugiura, Yuki, Yamasaki, Satoshi, Kinouchi, Chieko, Yonezawa, Taishi, Miyake, Kensuke, Sato, Naru, Tsuchiya, Akiho, Sasaki, Atsuo T, Jia, Yuhan, Li, Jingmei, Liu, Xiaoxiao, Schibler, Janet, Iwamura, Hiroyuki, Takizawa, Hitoshi, Tamura, Moe, Fukuyama, Tomofusa, Shikata, Shiori, Shibata, Tatsuhiro, O'Brien, Eric

2023

Overview

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. Synopsis This study describes the potent antileukemia effect of IMPDH inhibitors on MLL‐fusion leukemias, which is partly mediated by the overactivation of TLR‐NF‐kB‐Vcam1 pathway. MLL‐fusion leukemias are particularly susceptible to IMPDH inhibition. An alternate‐day administration of IMPDH inhibitors effectively suppresses MLL‐AF9‐driven leukemogenesis in vivo through myeloid differentiation without any devastating effect on immune function. IMPDH inhibition results in activation of TLR pathway and Vcam1 upregulation in MLL‐fusion leukemia cells. Combined treatment with IMPDH inhibitors and the TLR1/2 agonist shows potent antileukemia effects in vivo . Graphical Abstract This study describes the potent antileukemia effect of IMPDH inhibitors on MLL‐fusion leukemias, which is partly mediated by the overactivation of TLR‐NF‐kB‐Vcam1 pathway.

• Publisher: Nature Publishing Group UK,EMBO Press,John Wiley and Sons Inc,Springer Nature
• Subject: Acute myeloid leukemia / Antitumor activity / Apoptosis / Cell cycle / EMBO03 / EMBO18 / Enzyme Inhibitors - pharmacology / Epigenetics / Humans / Immune response / Immunosuppressive agents / Immunosuppressive Agents - therapeutic use / IMPDH inhibitor / Inosine monophosphate / Kinases / Leukemia / Leukemia, Myeloid, Acute - drug therapy / Leukemia, Myeloid, Acute - pathology / MLL‐fusion leukemia / Myeloid-Lymphoid Leukemia Protein - metabolism / NF-kappa B / NF-κB protein / Patients / Proteins / Signal transduction / TLR signaling / TLR1 protein / Toll-like receptors / TRAF6 protein / Tumors / Vcam1