SHP1 expression accounts for resistance to imatinib treatment in Philadelphia chromosome-positive cells derived from patients with chronic myeloid leukemia.

Publication Type:

Journal Article


Blood, Volume 118, Issue 13, p.3634-44 (2011)


2011, Adult, Aged, Antineoplastic Agents, Biomarkers, Pharmacological, Cell Line, Tumor, Center-Authored Paper, Clinical Research Division, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Leukemic, Humans, K562 Cells, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Male, Middle Aged, Philadelphia Chromosome, Piperazines, Protein Kinase Inhibitors, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Pyrimidines, September 2011, Tumor Markers, Biological, Young Adult


We prove that the tyrosine phosphatase SHP-1 plays a prominent role as resistance determinant of Imatinib (IMA) treatment response in Chronic Myelogenous Leukemia cell lines (sensitive/KCL22-S and resistant/KCL22-R). Indeed, SHP-1 expression is significantly lower in resistant than in sensitive cell line, in which co-immunoprecipitation analysis reveals the interaction between SHP-1 and a second tyrosine phosphatase SHP-2, a positive regulator of RAS/MAPK pathway. In KCL22-R SHP-1 ectopic expression restores both SHP1/SHP-2 interaction and IMA responsiveness; it also decreases SHP-2 activity after IMA treatment. Consistently, SHP-2 knocking-down in KCL22-R reduces either STAT3 activation or cell viability after IMA exposure. Therefore our data suggest that SHP-1 plays an important role in BCR-ABL independent IMA resistance modulating the activation signals that SHP-2 receives from both BCR/ABL and membrane receptor tyrosine kinases. The role of SHP-1 as a determinant of IMA sensitivity has been further confirmed in 60 consecutive untreated CML patients, whose SHP-1 mRNA levels were significantly lower in case of IMA treatment failure (p<0.0001). In conclusion, we suggest that SHP-1 could be a new biological indicator at baseline of IMA sensitivity in CML patients.