Eliminating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors
Yosuke Tanaka, Reina Takeda, Tsuyoshi Fukushima, Keiko Mikami, Shun Tsuchiya, Moe Tamura, Keito Adachi, Terumasa Umemoto, Shuhei Asada, Naoki Watanabe, Soji Morishita, Misa Imai, Masayoshi Nagata, Marito Araki, Hitoshi Takizawa, Tomofusa Fukuyama, Chrystelle Lamagna, Esteban S. Masuda, Ryoji Ito, Susumu Goyama, Norio Komatsu, Tomoiku Takaku, Toshio Kitamura
Abstract
Abstract 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.