Abnormal pi integrin function in cml progenitors is related to enhanced receptor attachment to the cytoskeleton

Academic Article

Abstract

  • Abnormal proliferation of malignant progenitors In chronic myetogenous leukemia (CML) may be related to defective 01 integrin-medlated adhesion and inhibition of proliferation. Nonnal integrin-mediated adhesion requires dynamic Interactions between receptors and the cytoskeleton. ki normal progenitor!, receptor capping occurs following antibody (Ab) mediated crossUnUng of β1 integrins. The lateral movement of integrin receptors to form caps requires normal receptor-cytoskeleton Interactions and is Inhibited by high concentrations of Cytochalasln D (Cyto D). In malignant CML progenitors, 01 Integrin capping Is significantly reduced, suggesting that abnormal receptor-cytosketetal interactions may contribute to defective integrin function. Interferon-a (IFN-a) can restore normal integrin-medlated adhesion and signaling, and normal Integrin capping, in CML progenitors. We have now further explored the nature of the defect in kttegrincytoskeMal Interactions In CML progenitors. We evaluated whether enhanced attachment to the cytoskeleton. with reduced receptor mobility, contributed to defective CML Integrin function. CML manrow CD34+ cells . were preincubatad with varying concentrations of Cyto D prior to receptor crosslinklng with nti-pl Integrin Ab and FITC-tagged secondary Ab and evaluated for receptor distribution. Low concentrations of Cyto D (that do not completely disrupt the actin cytoskeleton) have been shown to enhance Integrin receptor mobility. We observed that 01 Integrin capping in CML CD34+ cells was significantly enhanced, although not fully corrected, by low concentrations (0.2-0.5nM) of Cyto D (from 12+3.6% to 22.5+3.6%, n-4,p<0.007), but not with high concentrations (1.0-S.OM). CML progenitor adhesion to flbronectin was also significantly enhanced (p<0.05) by low, but not high, concentrations of Cyto D. However, In normal progenitors and IFN-o-tnated CML progenitors, capping and adhesion was not affected by low concentrations of Cyto D. and was inhibited by high concentrations. We also evaluated the Interaction between other cell surface receptors and the cytoskeleton In CML progenitors. Similar to 01 Integrins, capping of o4 and öS Integrins was déficient and was restored by IFN-a. In contrast, 02 integrins (CD11b) capping was reduced but was not restored by IFN-a, and capping of HLA-DR, CD33 and CD38 was normal. These studies suggest that enhanced cytoskeletal attachment and reduced receptor mobility may contribute to abnormal o4β1 and o501 integrin receptor function in CML progenitors and these defects may be partially correctable by IFN-a.
  • Published In

    Author List

  • Bhatia R; Munthe H; Vetfalllle CM
  • Start Page

  • 757
  • Volume

  • 25
  • Issue

  • 8