Growth factor stimulation enhances integrin-mediated migration but not adhesion of cml progenitors

Abstract

Abnormal progenitor circulation and extramedullary hematopoiesis are characteristic features of chronic myelogenous leukemia (CML). These abnormalities could be related to altered β1 integrin function in CML progenitors. β1 integrins play an important role in growth factor (GF) induced mobilization of normal progenitors from the bone marrow into the circulation. Although expressing β1-integrins at normal levels, CML progenitors demonstrate significantly reduced adhesion to stroma and fibronectin (FN). We evaluated the effect of GF stimulation on CML progenitor adhesion and migration on FN. GF modulation of β1 integrin-mediated adhesion was impaired in CML CFC. Normal CFC incubated with physiological concentrations of GF had significantly enhanced adhesion to FN compared with cells incubated without GF (30.4±4.6% vs. 14±3.6%, p<0.01), whereas CML CFC adhesion to FN was poor regardless of the presence or absence of GF (7.6±1.8% vs. 7.9±2.1%). Addition of IL-3, FL and other GF rapidly enhanced β1 integrin-mediated adhesion of normal CFC to FN, but did not increase CML CFC adhesion. On the other hand, CML CFC demonstrated increase migration across FN-coated transwells (5μm pores) compared with normal CFC (15.7±3.4% vs. 7.3±1.4%, p<0.05) as well as increased spontaneous migration across uncoated transwells (9.9±2.2% vs. 3.2±0.7%, p<0.05). Addition of SCF enhanced migration of normal CFC through uncoated and FN-coated transwells (9.2+1.8% and 19.1+4.1%). In contrast to its lack of effect on adhesion, SCF also enhanced CML CFC migration (FN-: 15.3±4.3% and FN+: 23.9±6.1%). The presence or absence of GF did not affect cell viability or integrin expression. Differential enhancement of migration but not adhesion in response to GF simulation could play a role in abnormal progenitor circulation and localization in CML.