SHP-1 expression accounts for resistance to imatinib treatment in Philadelphia chromosome–positive cells derived from patients with chronic myeloid leukemia
| Autor: | Tonia Buonomo, Nicola Esposito, Susan Branford, Timothy P. Hughes, Agostino Rodeo Sica, Deborah L. White, Margherita Ruoppolo, Jerald P. Radich, Marco Picardi, Fabrizio Pane, Giuseppe Saglio, Thea Kalebic, Anna Lucia Peluso, Luigi Del Vecchio, Concetta Quintarelli, Irene Colavita, Junia V. Melo, Rosanna Martinelli, Domenico Russo, Giovanni Martinelli, Luigia Luciano |
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| Přispěvatelé: | Esposito, N, Colavita, I, Quintarelli, C, Sica, Ar, Peluso, Al, Luciano, L, Picardi, Marco, DEL VECCHIO, Luigi, Buonomo, T, Hughes, Tp, White, D, Radich, Jp, Russo, D, Branford, S, Saglio, G, Melo, Jv, Martinelli, R, Ruoppolo, Margherita, Kalebic, T, Martinelli, G, Pane, Fabrizio, Esposito N., Colavita I., Quintarelli C., Sica A.R., Peluso A.L., Luciano L., Picardi M., Del Vecchio L., Buonomo T., Hughes T.P., White D., Radich J.P., Russo D., Branford S., Saglio G., Melo J.V., Martinelli R., Ruoppolo M., Kalebic T., Martinelli G., Pane F. |
| Rok vydání: | 2011 |
| Předmět: |
Male
Drug Resistance Biochemistry Biomarkers Pharmacological Piperazines Non-Receptor Type 6 Philadelphia Chromosome Chronic Leukemic Tumor Leukemia ABL Gene Expression Regulation Leukemic Protein Tyrosine Phosphatase Non-Receptor Type 6 Myeloid leukemia hemic and immune systems Hematology Middle Aged Benzamides embryonic structures Imatinib Mesylate Female Adult Aged Antineoplastic Agents Biomarkers Tumor Cell Line Tumor Drug Resistance Neoplasm Humans K562 Cells Leukemia Myelogenous Chronic BCR-ABL Positive Protein Kinase Inhibitors Pyrimidines Young Adult Cell Biology Immunology biological phenomena cell phenomena and immunity Tyrosine kinase medicine.drug medicine.medical_specialty animal structures chemical and pharmacologic phenomena Biology Philadelphia chromosome Cell Line Internal medicine medicine Pharmacological Imatinib medicine.disease Imatinib mesylate Endocrinology Gene Expression Regulation Cancer research Neoplasm BCR-ABL Positive Protein Tyrosine Phosphatase CHRONIC MYELOID LEUKEMIA (CML) Biomarkers Myelogenous Chronic myelogenous leukemia K562 cells |
| Zdroj: | Blood. 118:3634-3644 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2011-03-341073 |
| Popis: | 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 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 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. |
| Databáze: | OpenAIRE |
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