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.
Highlights
Leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) are quiescent, insensitive to BCR-ABL1 tyrosine kinase inhibitors (TKIs) and responsible for CML relapse
CML derived from bone marrow (BM) cells carrying G0 marker (G0M) was developed in about 3 weeks, and imatinib treatment prolonged the survival of leukemic mice (Fig. 1b), ensuring that G0M did not affect CML development or imatinib treatment
In this study, using a G0 marker (G0M)[43], we found that quiescent CML LSCs are highly enriched in G0M+CD27+CML LSK cells (DP cells)
Summary
Leukemia stem cells (LSCs) in chronic myeloid leukemia (CML) are quiescent, insensitive to BCR-ABL1 tyrosine kinase inhibitors (TKIs) and responsible for CML relapse. Inhibitor, is effective at suppressing the growth of imatinibresistant CML cell lines and bone marrow (BM) cells of imatinibresistant CML-chronic phase (CML-CP) patient bone marrow (BM) cells in vitro[32] These reports indicate that NF-κB activation is responsible for the TKI-resistance of CML LSCs. Notably, CML LSCs express higher levels of IL-1 receptors (IL1Rs) and are more sensitive to IL-1-induced NF-κB signaling than normal HSCs. the combination of a recombinant IL-1R antagonist (IL-1RA) with a TKI resulted in significantly greater inhibition of CML LSCs compared with the TKI alone[33]. These reports indicate that the IL-1R-NF-κB signal axis is important for the proliferation of CML LSCs
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