Eradicating chronic myeloid leukemia stem cells by IRAK1/4 inhibitors

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 novel G0 marker (G0M), we narrowed down CML LSCs as G0M- and CD27- double positive cells among the conventional CML LSCs. Whole transcriptome analysis revealed NF-κB activation via inflammatory signals in imatinib-insensitive quiescent CML LSCs. Blocking NF-κB signals by IRAK1/4 inhibitors together with imatinib eradicated mouse and human CML LSCs. Intriguingly, IRAK1/4 inhibitors attenuated PD-L1 expression on CML LSCs, and blocking PD-L1 together with imatinib also effectively eradicated CML LSCs in the presence of T cell immunity. Thus, IRAK1/4 inhibitors could eradicate 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.