Glycoconjugates are the most abundant and dynamic cell surface biomolecules forming the plasma membrane glycocalyx and critical for regulating key cell-cell and cell-matrix interactions. Their involvement in drug resistance, however, has received little attention. Precursor B-acute lymphoblastic leukaemia (BCP-ALL) can become insensitive to chemotherapy when supported by contact with bone marrow stromal cells.
We performed integrated omics approach combining transcriptomics, proteomics, glycoproteomics and glycomics on BCP-ALL cells surviving a 30-day vincristine chemotherapy treatment while in co-culture with bone marrow stromal cells to investigate the drug treatment resistant remodelling of the leukaemia glycocalyx. While the overall glycosylation changes were modest at best, gGlycoproteomics data suggested that just selected glycoproteins such as CD38 experience a significant site-specific shift in glycoforms in drug-resistant cells.
We used molecular dynamics modelling of glycosylated and unglycosylated CD38, an immunotherapy target in leukaemia, to understand the impact of glycosylation and the vincristine-induced changes to understand how CD38 glycoforms affect its structure and thus, function. Our modelling indicated that glycosylation glycoform dimers in drug-resistant cells are likely stabilized by protein-protein interactions. In addition, we uncover that in contrast to the current structure model of CD38 that lacks glycosylation the inclusion of the glycan-residues predicts a different subunit organisation of CD38. Therapeutic antibody binding to CD38 may be affected by its glycosylation, pointing to underappreciated contributions of glycan modifications to therapy and their drug resistance induced changes that could alter the pharmacological properties of immunotherapy targets.