SHP-1 expression accounts for resistance to imatinib treatment in Philadelphia chromosome-positive cells derived from patients with chronic myeloid leukemia

Nicola Esposito, Irene Colavita, Concetta Quintarelli, Agostino Rodeo Sica, Anna Lucia Peluso, Luigia Luciano, Marco Picardi, Luigi Del Vecchio, Tonia Buonomo, Timothy P. Hughes, Deborah White, Jerald P. Radich, Domenico Russo, Susan Branford, Giuseppe Saglio, Junia V. Melo, Rosanna Martinelli, Margherita Ruoppolo, Thea Kalebic, Giovanni MartinelliFabrizio Pane

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3634-3644
Number of pages11
JournalBlood
Volume118
Issue number13
DOIs
Publication statusPublished - 29 Sep 2011

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this