Eliminating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors

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-kappa B activation via inflammatory signals in imatinib-insensitive quiescent CML LSCs. Blocking NF-kappa B 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-kappa B 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-kappa B-PD-L1 signaling is critical to mediate imatinib resistance in LSCs and that combining imatinib with blocking this signalling pathway can eliminate LSCs.