title: SHP-1 expression accounts for resistance to imatinib treatment in Philadelphia chromosome-positive cells derived from patients with chronic myeloid leukemia.
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 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.
authors.affiliation: CEINGE Biotecnologie Avanzate, Naples, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Esposito
authors.forename: Irene
authors.initials: I
authors.lastname: Colavita
authors.forename: Concetta
authors.initials: C
authors.lastname: Quintarelli
authors.forename: Agostino Rodeo
authors.initials: AR
authors.lastname: Sica
authors.forename: Anna Lucia
authors.initials: AL
authors.lastname: Peluso
authors.forename: Luigia
authors.initials: L
authors.lastname: Luciano
authors.forename: Marco
authors.initials: M
authors.lastname: Picardi
authors.forename: Luigi
authors.initials: L
authors.lastname: Del Vecchio
authors.forename: Tonia
authors.initials: T
authors.lastname: Buonomo
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
authors.forename: Deborah
authors.initials: D
authors.lastname: White
authors.forename: Jerald P
authors.initials: JP
authors.lastname: Radich
authors.forename: Domenico
authors.initials: D
authors.lastname: Russo
authors.forename: Susan
authors.initials: S
authors.lastname: Branford
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Saglio
authors.forename: Junia V
authors.initials: JV
authors.lastname: Melo
authors.forename: Rosanna
authors.initials: R
authors.lastname: Martinelli
authors.forename: Margherita
authors.initials: M
authors.lastname: Ruoppolo
authors.forename: Thea
authors.initials: T
authors.lastname: Kalebic
authors.forename: Giovanni
authors.initials: G
authors.lastname: Martinelli
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Pane
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001549:Benzamides; D054316:Biomarkers, Pharmacological / Q000032:analysis / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D005260:Female; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects / Q000502:physiology; D006801:Humans; D000068877:Imatinib Mesylate; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010677:Philadelphia Chromosome; D010879:Piperazines / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D011743:Pyrimidines / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D054316:Biomarkers, Pharmacological; D014408:Biomarkers, Tumor; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6