Hippo/STK4 is downregulated in imatinib-resistant chronic myeloid leukemia and its restoration enhances apoptosis

Abstract

Chronic myeloid leukemia (CML) is a clonal hematologic disorder characterized by the presence of the BCR::ABL1 fusion gene and is frequently associated with imatinib mesylate (IM) treatment failure. Aberrant expression of some key genes in the Hippo signaling pathway has been reported in CML and is involved in its pathogenesis and drug resistance. However, the entire core components of the Hippo pathway have not been elucidated in IM-sensitive and IM-resistant CML patients. We then compared the gene expression levels of the core mediators in the Hippo signaling pathway in normal subjects and CML patients with IM-sensitive and IM-resistant phenotypes. Compared to the normal group, KIBRA, STK4, and YAP1 were significantly downregulated, while LATS1 and LATS2 were increased in CML patients. Intriguingly, the correlation analysis indicated that decreased STK4 expression was associated with anemia in CML patients, particularly those with IM-resistance. The selected gene, STK4, was ectopically overexpressed in the CML-derived K562 cell line to demonstrate the therapeutic potential. Overexpression of STK4 significantly enhanced IM-induced apoptosis of CML cells. These findings suggest that expression of the gene-encoding Hippo pathway could be used as an optional prognostic marker in CML patients and rescue of Hippo/STK4 can provide a therapeutic way for CML treatment.