Sialylation regulates migration in chronic lymphocytic leukemia

Abstract

Sialylation is the terminal addition of sialic acid to underlying glycans and plays a prominent role in cell adhesion and immune regulation. Sialylated structures found on adhesion molecules, such as CD49d, mediate the interactions between cancer cells and the microenvironment, facilitating metastatic seeding in target organs. Chronic lymphocytic leukemia (CLL) is a clonal B-cell malignancy characterized by the accumulation of CD5- positive B cells in the peripheral blood, bone marrow and lymph nodes. CLL cells proliferate mainly in the lymph node “proliferation centers”, where the microenvironment provides pro-survival signals. Thus, migration and homing into these protective niches play a crucial role in CLL biology. In recent years, therapeutic strategies aiming at inducing the egress of CLL cells from the lymph nodes and bone marrow into the circulation have been highly successful. In this study, the sialylation status of 79 untreated and 24 ibrutinibtreated CLL patients was characterized by flow cytometry. Moreover, the effect of sialic acid removal on migration was tested by a transwell assay. Finally, we examined the sialylation status of CD49d by Western blot analysis. We found that CLL cells are highly sialylated, particularly those characterized by an “activated” immune phenotype. Notably, sialylation regulates CLL migration through the post-translational modification of CD49d. Finally, we showed that therapeutic agents that induce CLL mobilization from their protective niches such as ibrutinib, modulate the levels of sialic acids. We propose that sialylation is an important regulator of CLL trafficking and may represent a novel target to further improve CLL therapy.

CD49d in chronic lymphocytic leukemia: a molecule with multiple regulation layers. Comment to “Sialylation regulates migration in chronic lymphocytic leukemia”

“…on the regulation of migration in chronic lymphocytic leukemia (CLL) cells by sialylation, recently published in Haematologica. 1 …”

“… 2 In the B-cell context, known sugar modifications include mannosylation of the B-cell receptor (BCR)-influencing antigen engagement and signaling, 3 and, as reported by Natoni’s group, sialylation of the CD49d integrin in multiple myeloma 4 and in CLL. 1 …”

“…As one of the major actors regulating CLL microenvironmental interactions, CD49d expression and function are regulated at multiple levels, both genetic and epigenetic, as well as through protein-protein cooperation and/or conformational changes. In this complex scenario, sialylation, as described by Natoni and colleagues, 1 may represent the last regulation identified of the many layers of biochemical modifications and/or physical interactions of CD49d with other molecules, which can eventually contribute to fine-tune CD49d-mediated activities such as migration and adhesion.…”

“…These (epi)genetic- and protein-regulated mechanisms, tightly intertwine with the recently described sialylation of CD49d in CLL cells, as reported by Natoni et al . 1 which provides a novel, post-translational layer of regulation of integrin dynamics in CLL.…”

“…We read with interest the study by Natoni et al on the regulation of migration in chronic lymphocytic leukemia (CLL) cells by sialylation, recently published in Haematologica. 1 In the study, the authors investigate the sialylation status of CLL cells, evaluating specific expression of α2-3 and α2-6 sialic acids, demonstrating that this particular modification is highly represented on CLL cells. 1 Furthermore, they show that sialylation can affect the migratory capacity of CLL cells toward VCAM-1 and fibronectin (FN), which, in turn, is effectively suppressed upon treatment with neuraminidase (a glycoside hydrolase specific for sialic acids).…”