Twisting IL-1 signaling to kill CML stem cells

Abstract

In this issue of Blood, Agerstam et al 1 and Zhang et al2 show that increased expression of the interleukin-1 receptor (IL-1R) complex confers leukemia stem cells (LSCs) from chronic myeloid leukemia (CML) with a selective growth and survival advantage over normal hematopoietic stem cells (HSCs).1,2 Furthermore, they provide evidence that blocking IL-1 signaling through IL-1 receptor antagonist (IL-1RA)2 or antibody-mediated therapy (anti-IL-1R accessory protein [anti-IL-1RAP])1 has the potential to lead to disease eradication at a stem cell level (see figure). This is extremely important because first-, second-, and third-generation BCR-ABL1 TKIs, although they are capable of inducing sustained molecular and deep molecular remission, are unable to kill quiescent LSCs. Thus, it is becoming evident that a better characterization of the specific pathways of LSCs could lead to the development of new therapies that, if not toxic, will selectively kill CML LSCs. The therapeutic relevance of such studies rests on the fact that a successful CML eradication therapy will not only prevent disease relapse upon TKI discontinuation but also release the majority of patients from life-long and economically challenging TKI therapy and, perhaps, will positively impact prognosis of those patients who become resistant to multiple TKIs and/or undergo blastic transformation.