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 and Toshio Kitamura ()
Additional contact information
Yosuke Tanaka: The Institute of Medical Science, The University of Tokyo
Reina Takeda: The Institute of Medical Science, The University of Tokyo
Tsuyoshi Fukushima: The Institute of Medical Science, The University of Tokyo
Keiko Mikami: The Institute of Medical Science, The University of Tokyo
Shun Tsuchiya: Juntendo University Graduate School of Medicine
Moe Tamura: The Institute of Medical Science, The University of Tokyo
Keito Adachi: The Institute of Medical Science, The University of Tokyo
Terumasa Umemoto: International Research Center for Medical Sciences, Kumamoto University
Shuhei Asada: The Institute of Medical Science, The University of Tokyo
Naoki Watanabe: Juntendo University Graduate School of Medicine
Soji Morishita: Juntendo University Graduate School of Medicine
Misa Imai: Juntendo University Graduate School of Medicine
Masayoshi Nagata: Juntendo University Graduate School of Medicine
Marito Araki: Juntendo University Graduate School of Medicine
Hitoshi Takizawa: International Research Center for Medical Sciences, Kumamoto University
Tomofusa Fukuyama: The Institute of Medical Science, The University of Tokyo
Chrystelle Lamagna: Rigel, South San Francisco
Esteban S. Masuda: Rigel, South San Francisco
Ryoji Ito: Central Institute for Experimental Animals
Susumu Goyama: The University of Tokyo
Norio Komatsu: Juntendo University Graduate School of Medicine
Tomoiku Takaku: Juntendo University Graduate School of Medicine
Toshio Kitamura: The Institute of Medical Science, The University of Tokyo

Nature Communications, 2022, vol. 13, issue 1, 1-13

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 G0 marker (G0M), we narrow down CML LSCs as G0M- 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.

Date: 2022
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DOI: 10.1038/s41467-021-27928-8

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