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- Title
Eliminating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors.
- Authors
Tanaka, Yosuke; Takeda, Reina; Fukushima, Tsuyoshi; Mikami, Keiko; Tsuchiya, Shun; Tamura, Moe; Adachi, Keito; Umemoto, Terumasa; Asada, Shuhei; Watanabe, Naoki; Morishita, Soji; Imai, Misa; Nagata, Masayoshi; Araki, Marito; Takizawa, Hitoshi; Fukuyama, Tomofusa; Lamagna, Chrystelle; Masuda, Esteban S.; Ito, Ryoji; Goyama, Susumu
- 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. 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.
- Subjects
CHRONIC myeloid leukemia; RNA sequencing; STEM cells; PROTEIN-tyrosine kinase inhibitors; INTERLEUKIN-1 receptors
- Publication
Nature Communications, 2022, Vol 13, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-021-27928-8