Abstract
STAT3 plays a pivotal role in the hematopoietic system, which constitutively activated by BCR–ABL via JAK and Erk/MAP-kinase pathways. Phospho-STAT3 was overexpressed in imatinib-resistant CML patients as relative to imatinib responsive ones. By activation of the STAT3 pathway, BCR–ABL can promote cell cycling, and inhibit differentiation and apoptosis. Ribosomal protein S27a (RPS27a) performs extra-ribosomal functions besides imparting a role in ribosome biogenesis and post-translational modifications of proteins. RPS27a can promote proliferation, regulate cell cycle progression and inhibit apoptosis of leukemia cells. However, the relationship between STAT3 and RPS27a has not been reported. In this study, we detected a significantly increased expression of STAT3 and RPS27a in bone marrow samples from CML-AP/BP patients compared with those from CML-CP. In addition, we also demonstrated that it was a positive correlation between the level of STAT3 and that of RPS27a. Imatinib-resistant K562/G01 cells expressed significantly higher levels of STAT3 and RPS27a compared with those of K562 cells. RPS27a could be transactivated by p-STAT3 through the specific p-STAT3-binding site located nt −633 to −625 and −486 to −478 of the RPS27a gene promoter in a dose-dependent manner. The transactivated RPS27a could decrease the percentage of apoptotic CML cells induced by imatinib. And the effect of STAT3 overexpression could be counteracted by the p-STAT3 inhibitor WP1066 or RPS27a knockdown. These results suggest that drugs targeting STAT3/p-STAT3/RPS27a combining with TKI might represent a novel therapy strategy in patients with TKI-resistant CML.
Highlights
Chronic myelogenous leukemia (CML) is a common hematologic malignancy, characterized by the formation of Philadelphia (Ph) chromosome and BCR-ABL fusion gene [1]
We found that STAT3 was up-regulated in the transition from CML patients in chronic phase (CML-CP) to CML-AP/BP and there was a positive correlation between the expression level of STAT3 and that of Ribosomal protein S27a (RPS27a)
We found that there was a striking increase of STAT3 and RPS27a mRNA expression in bone marrow samples from CML-AP/BP patients than that from CML-CP
Summary
Chronic myelogenous leukemia (CML) is a common hematologic malignancy, characterized by the formation of Philadelphia (Ph) chromosome and BCR-ABL fusion gene [1]. As a constitutively active tyrosine kinase, BCR-ABL protein gives rise to uncontrolled growth of myeloid cells in the bone marrow through a series of downstream pathways [2]. The tyrosine kinase inhibitor (TKI) imatinib is a specific molecular target-drug for the treatment of Ph chromosome-positive CML [3,4,5,6]. It is considered as one of the most effective drugs and the first-line treatment for CML, resistance to imatinib seems unavoidable and occurs frequently during its clinical application. Abnormal expression of some other genes (P-glycoprotein (p-gp), AXL, heat-shock protein 70 (Hsp-70), STAT3, STAT5, Cancerous inhibitor of protein phosphatase 2A (CIP2A), B cell-specific MLV inte-gration site-1 (BMI-1), ATP-binding cassette subfamily G member 2 (ABCG2) were highly expressed and SHP-1, Cyclin-Dependent Kinase Inhibitor 3 (CDKI3), Raf Kinase Inhibitor Protein (RKIP), NOTCH2 were lowly expressed) or alternative signaling pathways activation may contribute to imatinib resistance [11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26]
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