CML progenitor adhesion and adhesion-mediated proliferation inhibition is restored by tyrphostin ag957, a protein tyrosine kinase inhibitor with activity against the BCR-ABL kinase

Academic Article

Abstract

  • Normal progenitor proliferation is inhibited following βl integrin-mediated adhesion to ström a or fibronectin. Abnormal circulation and continuous proliferation of malignant CML progenitors may be related to their deficient integrin-mediated adhesion and proliferation inhibition. Tyrosine phosphorylation of cytoplasmic proteins important for integrin signaling by the BCR-ABL protein tyrosine kinase (PTK) may underlie defective integrin function in CML. We examined the effect of two PTK inhibitors, Tyrphostin AG957 which has anti-BCRABL PTK activity and Tyrphostin AG555, without anti-BCR/ABL PTK activity, on CML CFC adhesion and adhesion-mediated proliferation inhibition. Incubation of CD34+DR+ cells for 1 hour with the PTK inhibitor AG957 at concentrations above SOOnM inhibited growth of both CML and normal CFC whereas AG555 did not suppress CML or normal CFCs at concentrations as high as 25nM. Incubation of CML CD34+DR+ cells for one hour with SOOnM AG957, with anti-BCR-ABL PTK activity, did not affect CFC viability, but resulted in enhanced CML CFC adhesion to stroma, whereas preinctibation with AG555 did not change CML CFC adhesion. Neither AG957 or AG555 significantly affected adhesion of normal CFC to stroma. Thymidine suicide assays demonstrated that incubation with AG957 or AG555 did not alter the proliferation of CML CFC when evaluated in suspension. However, prolifération of CML CFC preincubated with AG957 and then cocultured with stroma was significantly reduced. Proliferation of control untreated CML CFC or CML CFC treated with AG555 was not reduced following stroma-comact. Neither AG957 or AG555 significantly affected normal CFC proliferation, regardless of the presence or absence of stroma. The above data support a role for protein tyrosine phosphorylation, mediated by the BCR-ABL PTK, in abnormal adhesion-mediated microenvironmental regulation of CML CFC proliferation.
  • Author List

  • Bhatia R; Verfaillie C
  • Start Page

  • 1131
  • Volume

  • 24
  • Issue

  • 9