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|Title:||SHP-1 expression accounts for resistance to imatinib treatment in Philadelphia chromosome-positive cells derived from patients with chronic myeloid leukemia|
Vaz de Melo, J.
|Citation:||Blood, 2011; 118(13):3634-3644|
|Publisher:||Amer Soc Hematology|
|Nicola Esposito... Timothy P. Hughes... Deborah White... Susan Branford... Junia V. Melo... et al.|
|Abstract:||We prove that the SH2-containing tyrosine phosphatase 1 (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 coimmunoprecipitation analysis shows 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 SHP-1/SHP-2 interaction and IMA responsiveness; it also decreases SHP-2 activity after IMAtreatment. 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 patients with chronic myelogenous leukemia, whose SHP-1 mRNA levels were significantly lower in case of IMA treatment failure (P < .0001). In conclusion, we suggest that SHP-1 could be a new biologic indicator at baseline of IMA sensitivity in patients with chronic myelogenous leukemia.|
|Keywords:||Cell Line, Tumor; K562 Cells; Philadelphia Chromosome; Humans; Piperazines; Pyrimidines; Antineoplastic Agents; Tumor Markers, Biological; Protein Kinase Inhibitors; Gene Expression Regulation, Leukemic; Drug Resistance, Neoplasm; Adult; Aged; Middle Aged; Female; Male; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Biomarkers, Pharmacological; Young Adult|
|Rights:||© 2011 by The American Society of Hematology|
|Appears in Collections:||Medicine publications|
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