Characterization of the laminin receptors integrin α3β1, integrin α6β1, integrin α7β1 and basal cell adhesion molecule in acute myeloid leukemia

Acute myeloid leukemia (AML) is a rapidly progressing type of blood cancer characterized by the accumulation of immature myeloid blasts in the bone marrow (BM) or peripheral blood (PB) that interfere with healthy hematopoiesis. During leukemogenesis, healthy hematopoietic stem and progenitor cells acquire genetic and epigenetic lesions leading to the transformation into their malignant counterpart, the leukemic stem cells (LSC). Despite tremendous progress in AML research over the past few decades, as well as refined chemotherapeutic treatment strategies, AML remains a disease with a poor prognosis and a five-year overall survival rate of only 30%.
One major challenge in treating AML patients is the persistence of drug-resistant LSC that survive chemotherapy and cause relapse. The BM niche has recently gained attention as a protective environment for leukemic cells and it has been recognized that interactions with the BM niche are crucial for promoting self-renewal and survival of AML cells. At the same time, AML cells remodel the BM niche, adapt it to their needs and create a pro-leukemic microenvironment. Consequently, AML cells express a variety of surface receptors to engage with BM niche cells and extracellular matrix proteins, such as laminins. Despite the association of laminin receptor expression with stemness in healthy hematopoiesis and with poor prognosis in several cancer entities, the role of laminin receptors in AML remains poorly understood.
This thesis provides a comprehensive characterization of the laminin receptors integrin α3β1, integrin α6β1, integrin α7β1 and basal cell adhesion molecule (BCAM) in AML. In addition to analyzing publicly available datasets, we used a flow cytometry approach to determine laminin receptor expression on primary BM and PB samples from a cohort of 60 AML patients, also in relation to stemness and prognosis. We found that high mRNA expression of all four laminin receptors correlated with poor overall survival. Notably, integrin α6 and α7 displayed the highest cell surface presentation among the laminin receptors examined and were expressed at higher levels on AML cells in comparison to healthy controls. Moreover, our results indicated that integrin α7 expression allows to distinguish between LSC and non-LSC populations and that integrin α7 surface expression further identifies a cell population with enhanced migratory potential. In contrast, integrin α6 contributed to laminin adhesion and therefore presumably to AML cell retention to the BM niche. Both, interfering with ECM interactions and targeting the migratory cell population may have therapeutic potential.