Journal Article

Eliminating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors

Takaku, Tomoiku, Kitamura, Toshio, Watanabe, Naoki, Lamagna, Chrystelle, Tanaka, Yosuke, Asada, Shuhei, Fukushima, Tsuyoshi, Masuda, Esteban S., Goyama, Susumu, Tsuchiya, Shun, Adachi, Keito, Morishita, Soji, Araki, Marito, Ito, Ryoji, Nagata, Masayoshi, Komatsu, Norio, Takizawa, Hitoshi, Tamura, Moe, Fukuyama, Tomofusa, Takeda, Reina, Imai, Misa, Mikami, Keiko, Umemoto, Terumasa

2022

Overview

Leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) are quiescent, insensitive to BCR-ABL1 tyrosine kinase inhibitors (TKIs) and responsible for CML relapse. Therefore, eradicating quiescent CML LSCs is a major goal in CML therapy. Here, using a G 0 marker (G 0 M), we narrow down CML LSCs as G 0 M- and CD27- double positive cells among the conventional CML LSCs. Whole transcriptome analysis reveals NF-κB activation via inflammatory signals in imatinib-insensitive quiescent CML LSCs. Blocking NF-κB signals by inhibitors of interleukin-1 receptor-associated kinase 1/4 (IRAK1/4 inhibitors) together with imatinib eliminates mouse and human CML LSCs. Intriguingly, IRAK1/4 inhibitors attenuate PD-L1 expression on CML LSCs, and blocking PD-L1 together with imatinib also effectively eliminates CML LSCs in the presence of T cell immunity. Thus, IRAK1/4 inhibitors can eliminate CML LSCs through inhibiting NF-κB activity and reducing PD-L1 expression. Collectively, the combination of TKIs and IRAK1/4 inhibitors is an attractive strategy to achieve a radical cure of CML. Leukemic stem cells (LSCs) in chronic myeloid leukemia are resistant to imatinib and therefore are a cause of relapse. The authors show that IRAK1/4-NF-κB-PD-L1 signaling is critical to mediate imatinib resistance in LSCs and that combining imatinib with blocking this signalling pathway can eliminate LSCs.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/100 / 13/2 / 13/31 / 13/44 / 13/51 / 14/1 / 14/35 / 14/63 / 38/91 / 42/109 / 631/67/1059/2326 / 631/67/71 / 64/60 / 692/4028/67/1990/283/1896 / 96/106 / Animals / Antineoplastic Agents - pharmacology / CD27 antigen / Chronic Disease / Chronic myeloid leukemia / Drug Resistance, Neoplasm - drug effects / Female / Fusion Proteins, bcr-abl - metabolism / Humanities and Social Sciences / Humans / Imatinib / Imatinib Mesylate - pharmacology / Immune Checkpoint Inhibitors - pharmacology / Inflammation / Inhibitor drugs / Inhibitors / Interleukin 1 / Interleukin-1 Receptor-Associated Kinases - drug effects / Interleukin-1 Receptor-Associated Kinases - metabolism / IRAK protein / Kinases / Leukemia / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - drug therapy / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - genetics / Leukemia, Myelogenous, Chronic, BCR-ABL Positive - metabolism / Leukemia, Myeloid - drug therapy / Lymphocytes / Lymphocytes T / Male / Mice / Middle Aged / multidisciplinary / Myeloid leukemia / Neoplastic Stem Cells - metabolism / NF-κB protein / PD-L1 protein / Protein Kinase Inhibitors - pharmacology / Protein-tyrosine kinase / Science / Science (multidisciplinary) / Signal transduction / Signaling / Stem cell transplantation / Stem cells / Transcriptomes / Tyrosine