Department of Medical Oncology, Inselspital, Bern University Hospital, University of Bern, Bern 3010, Switzerland.
Tumor Immunology, Department for BioMedical Research (DBMR), University of Bern, Bern 3008, Switzerland.
Sci Signal. 2023 Aug 29;16(800):eadd7705. doi: 10.1126/scisignal.add7705.
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 CML and CD34 AML cells harboring and 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.
细胞干性的特征是静止、多能性和长期自我更新能力。耐药性白血病干细胞（LSCs）是慢性和急性髓系白血病（CML 和 AML）患者复发的主要原因。然而，相同的信号通路经常在 LSCs 和正常造血干细胞（HSCs）中支持干性，这使得 LSCs 难以成为治疗靶点。在细胞系和患者样本中，我们发现白细胞介素 33（IL-33）信号仅以特定亚型的方式在白血病细胞中促进干性。IL-33 受体 ST2 在表达 和 易位或 9q 染色体缺失 [del(9q)] 的 CD34 CML 和 CD34 AML 细胞表面丰富。ST2 的细胞表面丰度在其他白血病亚型和 HSCs 中较低或不存在，与干性、激活的 Wnt 信号和抑制的 Notch 信号相关。IL-33-ST2 信号通过激活 Wnt、MAPK 和 NF-κB 信号促进 AML1/ETO-、DEK/NUP214-和 BCR/ABL1 阳性 LSCs 在培养中和小鼠中的维持和扩增。Wnt 信号及其对 Notch 途径的抑制上调了编码 ST2 的基因的表达，从而形成了细胞自主循环。IL-33-ST2 信号促进了 CML 细胞对酪氨酸激酶抑制剂（TKI）尼罗替尼和 AML 细胞对标准化疗的耐药性。因此，抑制 IL-33-ST2 信号可能靶向 LSCs，以克服这些白血病亚型对化疗或 TKI 的耐药性。
