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Sci Signal ; 16(800): eadd7705, 2023 08 29.
Artigo em Inglês | MEDLINE | ID: mdl-37643244

RESUMO

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.


Assuntos
Interleucina-33 , Leucemia Mieloide , Animais , Camundongos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-33/genética , NF-kappa B , Via de Sinalização Wnt
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