Shp-2-mediated Imatinib-resistant Mechanism In Chronic Myeloid Leukemia Cells

Chronic myeloid leukemia(CML)is a clonal hematopoietic cell malignancy associated with the reciprocal t(9;22)(q34;q11)chromosome translocation.Translocation of c-abl gene located on chromosome 9 to the bcr gene on chromosome 22 generates a fusion oncogene bcr/abl.The chromosome contains the bcr/abl is termed as Ph chromosome.The fusion oncogene bcr/abl encodes chimeric tyrosine kinase BCR-ABL,which has the stronger tyrosine kinase activity than wide type kinase c-ABL.Constitutively active BCR-ABL kinase can induce transformation by inhibiting cell death and inducing cell proliferation,which plays a crucial role in CML.Up to day the main treatment schedule is to use tyrosine kinase inhibitor(TKI)to suppress BCR-ABL kinase activity.For example,imatinib is a typical clinic drug for CML therapy.However,CML patients are mostly resistant to imatinib because of mutation and increased expression of bcr/abl or CML stem cells.In this study,comparison of imatinib-sensitive CML cell line K562 with a resistant cell line K562/G revealed that the phosphorylated shp-2 is higher obviously in K562/G cells than that in K562 cells.BCR-ABL and shp-2 interacts each other in K562 cells,while no interaction was found in K562/G cells.PHPS1,the specific shp-2 inhibitor,showed no cytotoxicity in either K562 or K562/G cells.Interestingly,combining PHPS1 with imatinib greatly enhanced apoptosis in K562/G cells and inhibited the in vivo growth of K562/G cells.Mechanismly,co-treatment of imatinib and PHPS1 supressed the PI3K-AKT-mTOR cell signaling pathway mediated by BCR-ABL and the RAF-MEK-ERK cell signaling pathway mediated by shp-2 simultaneously.Our findings revealed the function of shp-2 in imatinib-resisitant CML cells,which might be helpful to overcome imatinib resistence in CML.