AI Article Synopsis

  • Reduced responsiveness to chemotherapy in precursor B-acute lymphoblastic leukemia (BCP-ALL) can be identified by the presence of minimal residual disease cells after 28 days of treatment, which is influenced by the supportive bone marrow microenvironment.
  • The study found that these drug-tolerant cells showed significant changes in their glycocalyx, including shifts in glycan structures and reduced sialylation, indicating how their surface proteins might adapt to survive chemotherapy.
  • Specific proteins, such as HLA-DRA and CD38, were identified as having differential glycosylation patterns, suggesting that these changes in glycosylation could be potential targets for developing new treatments against drug-resistant leukemia.

Article Abstract

Reduced responsiveness of precursor B-acute lymphoblastic leukemia (BCP-ALL) to chemotherapy can be first detected in the form of minimal residual disease leukemia cells that persist after 28 days of initial treatment. The ability of these cells to resist chemotherapy is partly due to the microenvironment of the bone marrow, which promotes leukemia cell growth and provides protection, particularly under these conditions of stress. It is unknown if and how the glycocalyx of such cells is remodelled during the development of tolerance to drug treatment, even though glycosylation is the most abundant cell surface post-translational modification present on the plasma membrane. To investigate this, we performed analysis of BCP-ALL cells that survived a 30-day vincristine chemotherapy treatment while in co-culture with bone marrow stromal cells. Proteomics showed decreased levels of some metabolic enzymes. Overall glycocalyx changes included a shift from Core-2 to less complex Core-1 O-glycans, and reduced overall sialylation, with a shift from α2-6 to α2-3 linked Neu5Ac. Interestingly, there was a clear increase in bisecting complex N-glycans with a concomitant increased mRNA expression of , the only enzyme known to form bisecting N-glycans. These small but reproducible quantitative differences suggest that individual glycoproteins become differentially glycosylated. Glycoproteomics confirmed glycosite-specific modulation of cell surface and lysosomal proteins in drug-tolerant BCP-ALL cells, including HLA-DRA, CD38, LAMP1 and PPT1. We conclude that drug-tolerant persister leukemia cells that grow under continuous chemotherapy stress have characteristic glycotraits that correlate with and perhaps contribute to their ability to survive and could be tested as neoantigens in drug-resistant leukemia.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11370571PMC
http://dx.doi.org/10.1101/2024.08.22.609211DOI Listing

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