VLA-4 Expression and Activation in B Cell Malignancies: Functional and Clinical Aspects

Abstract

Lineage commitment and differentiation of hematopoietic cells takes place in well-defined microenvironmental surroundings. Communication with other cell types is a vital prerequisite for the normal functions of the immune system, while disturbances in this communication support the development and progression of neoplastic disease. Integrins such as the integrin very late antigen-4 (VLA-4; CD49d/CD29) control the localization of healthy as well as malignant B cells within the tissue, and thus determine the patterns of organ infiltration. Malignant B cells retain some key characteristics of their normal counterparts, with B cell receptor (BCR) signaling and integrin-mediated adhesion being essential mediators of tumor cell homing, survival and proliferation. It is thus not surprising that targeting the BCR pathway using small molecule inhibitors has proved highly effective in the treatment of B cell malignancies. Attenuation of BCR-dependent lymphoma-microenvironment interactions was, in this regard, described as a main mechanism critically contributing to the efficacy of these agents. Here, we review the contribution of VLA-4 to normal B cell differentiation on the one hand, and to the pathophysiology of B cell malignancies on the other hand. We describe its impact as a prognostic marker, its interplay with BCR signaling and its predictive role for novel BCR-targeting therapies, in chronic lymphocytic leukemia and beyond.

Keywords: B cell differentiation; B cell receptor; Bruton’s tyrosine kinase; CD49d; CLL; adhesion; chronic lymphocytic leukemia; integrin; leukemia; lymphoma; therapy; tumor microenvironment.

Scheme 1

The integrin family of adhesion molecules. (A) Combinations of α and β subunits in mammals. In I domain containing integrins (e.g., LFA-1, see Section 5), the I-domain is added to the beta propeller of the α subunit, completely blocking access to the ligand-binding domain of the resting integrin. (B) Schematic structure of the VLA-4 integrin and its domains.

Scheme 2

Integrin signaling pathways in B cells. Affinity upregulation can be initiated by various cellular receptors, e.g., chemokine receptors or the B cell receptor (BCR). The signaling cascades commonly converge on PI3K and PLCγ, and at the end of the cascade, adaptor proteins, in leukocytes talin-1 and kindlin-3, bind to the intracellular domain of the integrin beta chain. This leads to affinity upregulation and/or extension and/or clustering, with the result of increased cellular adhesiveness. BCR: B cell receptor; GPCR: G protein-coupled receptor; BTK: Bruton’s tyrosine kinase; PI3K: Phosphatidylinositide 3-Kinase; PLCγ: Phospholipase Cγ; SFKs: Src family kinases; Syk: Spleen tyrosine kinase; FAK: Focal adhesion kinase; Pyk2: Proline-rich tyrosine kinase 2.

Scheme 3

Affinity states of VLA-4. Activation of the receptor by intracellular signaling (so-called inside-out activation) can induce affinity upregulation and/or extension; ligand-binding leads to exposure of the hybrid domain.

Scheme 4

Modes of VLA-4 activation. An overall increase in cellular adhesiveness can be achieved by either of the following processes: (A) affinity modulation of the ligand binding domain, leading to increased stability of receptor-ligand bonds (B) extension of the integrin molecule, leading to an increased accessibility of the ligand-binding site for surface-bound ligands or (C) clustering of integrins on the cell surface, leading to a local increase in the number of receptor–ligand bonds. Cellular activation often involves a combination of two or three of these processes; however, they can also occur separately.