Fibronectin interaction with α4β1 integrin prevents apoptosis in B cell chronic lymphocytic leukemia: correlation with Bcl-2 and Bax

Abstract

B cell chronic lymphocytic leukemia (B-CLL) consists of the accumulation of malignant cells that apparently escape normal apoptotic regulation. We have studied the role of ␣4␤1 integrin/fibronectin interaction in preventing apoptosis of these cells in vitro. B cells from 16 patients showed constant expression of ␣4␤1 and little or no ␣5␤1. B-CLL cells cultured on fibronectin or two previously described fibronectin recombinant fragments (H89 and H0) which contain the ligands for ␣4␤1, consistently showed higher viability than control cells cultured on poly-lysine. The H89 fragment, containing the high affinity ligand CS-1, was the most efficient substrate with mean cell viability values of 72, 60 and 35% at days 2, 5 and 8 of culture, respectively. For control cells these values were 40, 27 and 15%, respectively. Parallel cell cycle analysis confirmed these results. The anti-apoptotic effect required direct contact with immobilized substrata since it was not observed when using B-CLL conditioned media alone or when clustering ␣4␤1 with specific mAbs in suspension. Quantitation of the apoptosis regulatory proteins Bcl-2 and Bax revealed that cells cultured on the H89 fragment showed high/moderate levels of Bcl-2 (with some interpatient variation) and low levels of Bax resulting in an elevated Bcl-2/Bax ratio. These results indicate that adhesion of B-CLL cells to fibronectin upregulate the Bcl-2/Bax ratio and this may contribute to the anti-apoptotic effect induced via ␣4␤1 integrin.

In vivo CD44‐CD49d complex formation in autoimmune disease has consequences on T cell activation and apoptosis resistance

“…Instead, a subthreshold dose of anti-CD3 increased apoptosis susceptibility in control LNC and this was not influenced by CD44 or CD49d cross-linking. Signaling through CD49d induces B cell survival by upregulation of Bcl2 and Bcl-Xl in germinal centers and prevents apoptosis of B-CLL cells [59][60][61]. In these studies the role of FAK was not evaluated.…”

The class II tumor-suppressor gene RARRES3 is expressed in B cell lymphocytic leukemias and down-regulated with disease progression

“…20,21 CD5 + malignant B-lymphocytes were purified from the peripheral blood of B-CLL samples as previously described. 22 …”

CD34+ marrow progenitors from MDS patients with high levels of intramedullary apoptosis have reduced expression of α4β1 and α5β1 integrins

“…The interactions between a4b1 and a5b1 receptors on leukemic cells and their stromal ligands have also been intensively studied both in acute and chronic leukemia. [13][14][15][16][17] For example, the interaction of a4b1 with fibronectin has been shown to promote the survival of AML blasts, and may therefore be of crucial importance in the persistence of minimal residual disease. 13 Given their importance in normal and leukemic hematopoiesis, we were interested in the expression and function of a4b1 and a5b1 on HPC in myelodysplastic syndromes (MDS): a bone marrow failure disorder with a high propensity for leukemic transformation.…”