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 the 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 over-expressed 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.

Co-culture model of B-cell acute lymphoblastic leukemia recapitulates a transcription signature of chemotherapy-refractory minimal residual disease

“…The down-regulated genes were involved in cell division and the cell cycle, while the up-regulated genes were enriched in cell adhesion and regulation of cell differentiation. These data are consistent with other publications that have also reported an increase in cellular adhesion makers in models in which leukemic cells have been cultured with non-malignant adherent cells [18][19][20] . We then conducted a Gene Set Enrichment Analysis (GSEA) to examine the overall expression changes for HALLMARK gene sets defined in MsigDB (FDR q-val < 0.05 and enrichment > 1.5).…”

Transcriptome Analysis Identifies LINC00152 as a Biomarker of Early Relapse and Mortality in Acute Lymphoblastic Leukemia

“…Our co-expression analysis revealed that LINC00152 regulates genes involved in substrate cellular adhesion processes, one of the main biological mechanisms associated with relapse and chemoresistance in ALL. Chemoresistance has been addressed in several studies as one of the most important mechanisms of relapse and death in ALL [40][41][42]. Taking together, these data and our findings regarding the association between LINC00152 high expression and the high risk of relapse suggest that LINC00152 could be potentially involved in chemoresistance; however, functional studies are required to prove these remarks.…”

DT2216—a Bcl-xL-specific degrader is highly active against Bcl-xL-dependent T cell lymphomas

“…This could involve the suppression of pro-apoptotic factors through various soluble factors, cell adhesion molecules, and extracellular matrix molecules. In fact, previous studies have implicated a range of factors, including CXCL12/CXCR4, NOTCH ligands and receptors, VCAM-1/VLA-4 and 5, fibronectin/VLA-4 and 5, hyaluronate and collagen/CD44 [38,39]. Alternatively, TCL cells may upregulate other Bcl-2 anti-apoptotic proteins to compensate for the loss of Bcl-xL, as observed in patients who developed adaptive resistance after long-term responses to venetoclax [40,41].…”