Integrin-Mediated Adhesion and Chemoresistance of Acute Lymphoblastic Leukemia Cells Residing in the Bone Marrow or the Central Nervous System

Abstract

Acute Lymphoblastic Leukemia (ALL) is the most common cancer in childhood. Despite a significantly improved prognosis over the last decade with a 5-years survival rate of ∼90%, treatment-related morbidity remains substantial and relapse occurs in 10-15% of patients (1). The most common site of relapse is the bone marrow, but early colonization and subsequent reoccurrence of the disease in the central nervous system (CNS) also occurs. Integrins are a family of cell surface molecules with a longstanding history in cancer cell adherence, migration and metastasis. In chronic lymphoblastic leukemia (CLL), the VLA-4 integrin has been acknowledged as a prognostic marker and mounting evidence indicates that this and other integrins may also play a role in acute leukemia, including ALL. Importantly, integrins engage in anti-apoptotic signaling when binding extracellular molecules that are enriched in the bone marrow and CNS microenvironments. Here, we review the current evidence for a role of integrins in the adherence of ALL cells within the bone marrow and their colonization of the CNS, with particular emphasis on mechanisms adding to cancer cell survival and chemoresistance.

Targeting chemokines for acute lymphoblastic leukemia therapy

“…In addition to the extensively studied BM microenvironment, the extramedullary microenvironments are also critical in the development and relapse of ALL [ 17 ]. CNS can protect blast cells from systemic chemotherapy [ 18 ], resulting in 10–30% of CNS relapse [ 19 ]. In T-ALL, chemokine receptors CCR7 and CXCR4 were associated with CNS infiltration of T-ALL cells [ 20 , 21 ].…”

Notch Signaling in the Bone Marrow Lymphopoietic Niche

“…Another important, though understudied, component of the BM niche is the extra-cellular matrix (ECM), which has been proposed to regulate both HSPCs and leukemia cells (201)(202)(203)(204). The ECM is a vital component of structural and signaling mechanisms in all tissues and consists of collogens, proteoglycans, and glycoproteins (205)(206)(207).…”

The Impact of Small Extracellular Vesicles on Lymphoblast Trafficking across the Blood-Cerebrospinal Fluid Barrier In Vitro

“…Furthermore, the exosomal expression of integrin α5 and αV was associated to brain metastatic melanoma [34]. In pediatric ALL, various integrins expressed on lymphoblasts were linked to CNS disease and even associated to potential routes of infiltration [35]. Given that the receptor repertoire of exosomes resembles parental cells, it is yet to elucidate whether the above-mentioned findings may also be mediated via leukemia-derived exosomes.…”

“…Lymphocyte homeostasis within the CNS compartment during healthy state is orchestrated by the BCSFB, and T-cells predominate the CSF [19,45]. Of note, pathways driving T-cell attraction to the CNS also underlie CNS infiltration of ALL, including the expression of C-C chemokine receptor type 7 (CCR7), P-selectin glycoprotein ligand 1 (PSGL-1), and integrins [35,[46][47][48]. When the predilection of CNS involvement in T-ALL hijacks these pathways [18], the BCSFB within the choroid plexus might well represent a significant gate into the CNS.…”