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Type: Journal article
Title: SHP-1 expression accounts for resistance to imatinib treatment in Philadelphia chromosome-positive cells derived from patients with chronic myeloid leukemia
Author: Esposito, N.
Colavita, I.
Quintarelli, C.
Sica, A.
Peluso, A.
Luciano, L.
Picardi, M.
Vecchio, L.
Buonomo, T.
Hughes, T.
White, D.
Radich, J.
Russo, D.
Branford, S.
Saglio, G.
Vaz de Melo, J.
Martinelli, R.
Ruoppolo, M.
Kalebic, T.
Martinelli, G.
et al.
Citation: Blood, 2011; 118(13):3634-3644
Publisher: Amer Soc Hematology
Issue Date: 2011
ISSN: 0006-4971
Statement of
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
Antineoplastic Agents
Protein Kinase Inhibitors
Gene Expression Regulation, Leukemic
Drug Resistance, Neoplasm
Middle Aged
Leukemia, Myelogenous, Chronic, BCR-ABL Positive
Protein Tyrosine Phosphatase, Non-Receptor Type 6
Biomarkers, Pharmacological
Young Adult
Biomarkers, Tumor
Imatinib Mesylate
Rights: © 2011 by The American Society of Hematology
DOI: 10.1182/blood-2011-03-341073
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