IL-33–ST2 signaling promotes stemness in subtypes of myeloid leukemia cells through the Wnt and Notch pathways

Cell stemness is characterized by quiescence, pluripotency, and long-term self-renewal capacity. Therapy-resistant leukemic stem cells (LSCs) are the primary cause of relapse in patients with chronic and acute myeloid leukemia (CML and AML). However, the same signaling pathways frequently support stemness in both LSCs and normal hematopoietic stem cells (HSCs), making LSCs difficult to therapeutically target. In cell lines and patient samples, we found that interleukin-33 (IL-33) signaling promoted stemness only in leukemia cells in a subtype-specific manner. The IL-33 receptor ST2 was abundant on the surfaces of CD34 + BCR/ABL1 CML and CD34 + AML cells harboring AML1/ETO and DEK/NUP214 translocations or deletion of chromosome 9q [del(9q)]. The cell surface abundance of ST2, which was lower or absent on other leukemia subtypes and HSCs, correlated with stemness, activated Wnt signaling, and repressed Notch signaling. IL-33–ST2 signaling promoted the maintenance and expansion of AML1/ETO–, DEK/NUP214–, and BCR/ABL1–positive LSCs in culture and in mice by activating Wnt, MAPK, and NF-κB signaling. Wnt signaling and its inhibition of the Notch pathway up-regulated the expression of the gene encoding ST2, thus forming a cell-autonomous loop. IL-33–ST2 signaling promoted the resistance of CML cells to the tyrosine kinase inhibitor (TKI) nilotinib and of AML cells to standard chemotherapy. Thus, inhibiting IL-33–ST2 signaling may target LSCs to overcome resistance to chemotherapy or TKIs in these subtypes of leukemia. The cytokine receptor ST2 perpetuates a stemness-promoting loop in leukemia. Leukemic stem cells (LSCs) are resistant to various therapies and promote relapse in many chronic and acute leukemias. However, targetable pathways in this cell type also support normal hematopoietic stem cells (HSCs). Naef et al . identified a mechanism on which LSCs were selectively dependent. Fusion proteins that drive leukemias, such as AML1-ETO and BCR-ABL, promoted LSC proliferation through a self-perpetuating loop involving Wnt signaling and ST2, a receptor for the cytokine IL-33. ST2 was not detected on normal HSCs, indicating a potentially cell-targeted approach for more durable treatment outcomes in patients. —Leslie K. Ferrarelli