Eviction from the sanctuary: Development of targeted therapy against cell adhesion molecules in acute lymphoblastic leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is a malignant hematological disease afflicting hematopoiesis in the bone marrow. While 80%-90% of patients diagnosed with ALL will achieve complete remission at some point during treatment, ALL is associated with high relapse rate, with a 5-year overall survival rate of 68%. The initial remission failure and the high rate of relapse can be attributed to intrinsic chemoprotective mechanisms that allow persistence of ALL cells despite therapy. These mechanisms are mediated, at least in part, through the engagement of cell adhesion molecules (CAMs) within the bone marrow microenvironment. This review assembles CAMs implicated in protection of leukemic cells from chemotherapy. Such studies are limited in ALL. Therefore, CAMs that are associated with poor outcomes or are overexpressed in ALL and have been shown to be involved in chemoprotection in other hematological cancers are also included. It is likely that these molecules play parallel roles in ALL because the CAMs identified to be a factor in ALL chemoresistance also work similarly in other hematological malignancies. We review the signaling mechanisms activated by the engagement of CAMs that provide protection from chemotherapy. Development of targeted therapies against CAMs could improve outcome and raise the overall cure rate in ALL.

Keywords: Acute lymphoblastic leukemia; Bone marrow; Cell adhesion molecules; Chemoresistance; Targeted therapy.

Fig. 1

A schematic showing the significance of minimal residual disease in determining prognosis in ALL.

Fig. 2

Pictorial representation of elements in the normal bone marrow microenvironment. The bone marrow microenvironment (BM) contains multiple cell types such as osteoblasts, osteoclasts, endothelial cells, mesenchymal stromal cells, fibroblasts and adipocytes that can interact with normal hematopoietic stem cells (HSCs) and control hematopoiesis and quiescence. ECM proteins, specifically fibronectin and osteopontin, and soluble factors such as SDF-1 and galectins (green spheres).

Fig. 3

Pictorial representation of CAMs on leukemic cells and their cognate interacting partners on cells within the bone marrow microenvironment. The numbers in superscript correspond to the citation describing the particular interaction.

Fig. 4

Representation of CAMs mediating ALL cell adhesion to different ECM proteins. The numbers in superscript correspond to the citation describing the particular interaction.

Fig. 5

Pictorial representation of the mechanisms of drugs targeting VLA-4. VLA-4 binds to its target VCAM-1 on bone marrow stromal cells or to ECM proteins such as osteopontin and fibronectin. This interaction activates pro-survival signaling pathways such as 1) NF-κb, 2) Src/MAPK and 3) PI3K/Akt. Disruption of these interactions by Natalizumab (Black Ys), a monoclonal antibody that targets VLA-4, or AS101 (black spheres), which oxidizes adjacent thiol residues in the exofacial domain of VLA-4 molecules. This prevents target binding and causes cytoskeletal and conformational changes in the VLA-4 molecule, results in inhibition of these pathways (shown by red crosses).

Fig. 6

Pictorial representation of the signaling pathway activated by VLA-5 binding to fibronectin. This interaction mediates the binding of scaffolding protein RACK1 to VLA-5 which recruits protein phosphatase PP2A. PP2A dephosphorylates GSK-3β on Ser 9 resulting in its activation. Activated GSK-3β signals via MAPK pathway to induce chemoresistance.