Novel therapeutic strategy for targeting chronic myeloid leukemia stem cells via IRAK1/4 inhibition

Abstract

Chronic myeloid leukemia (CML) stem cells have been identified to promote CML relapse due to their quiescent cell cycle and tyrosine kinase inhibitor resistance. Therefore, their eradication is important for the cure of CML. We herein identified the quiescent CML stem cell fraction using a G0 marker that can visualize quiescent cells. Whole-transcriptome analysis of imatinib-resistant, quiescent CML stem cells revealed that NF-κB is activated via inflammatory signals in the same cells. The combination of imatinib and an inhibitor of this inflammatory signal (IRAK1/4 inhibitor) effectively eliminated CML stem cells and attenuated PD-L1 expression in CML stem cells. Furthermore, the combination of anti-PD-L1 antibody and imatinib effectively eliminated CML stem cells in the presence of T-cell immunity, indicating the importance of creating an environment in which T cells can attack CML stem cells. Thus, IRAK1/4 inhibitors exert two effects: blocking CML stem cell survival and proliferation signals by inhibiting NF-κB and blocking T cell immune evasion by reducing PD-L1 expression in CML stem cells. Collectively, their combination may be one of the attractive strategies for achieving a radical cure for CML. Discussions regarding the possibility of future medications seem warranted.