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Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia
Normal early human B-cell development from lymphoid progenitors in the bone marrow depends on instructions from elements in that microenvironment that include stromal cells and factors secreted by these cells including the extracellular matrix. Glycosylation is thought to play a key role in such int...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967368/ https://www.ncbi.nlm.nih.gov/pubmed/35371997 http://dx.doi.org/10.3389/fonc.2022.828041 |
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author | Zhang, Mingfeng Qi, Tong Yang, Lu Kolarich, Daniel Heisterkamp, Nora |
author_facet | Zhang, Mingfeng Qi, Tong Yang, Lu Kolarich, Daniel Heisterkamp, Nora |
author_sort | Zhang, Mingfeng |
collection | PubMed |
description | Normal early human B-cell development from lymphoid progenitors in the bone marrow depends on instructions from elements in that microenvironment that include stromal cells and factors secreted by these cells including the extracellular matrix. Glycosylation is thought to play a key role in such interactions. The sialyltransferase ST6Gal1, with high expression in specific hematopoietic cell types, is the only enzyme thought to catalyze the terminal addition of sialic acids in an α2-6-linkage to galactose on N-glycans in such cells. Expression of ST6Gal1 increases as B cells undergo normal B-lineage differentiation. B-cell precursor acute lymphoblastic leukemias (BCP-ALLs) with differentiation arrest at various stages of early B-cell development have widely different expression levels of ST6GAL1 at diagnosis, with high ST6Gal1 in some but not in other relapses. We analyzed the consequences of increasing ST6Gal1 expression in a diagnosis sample using lentiviral transduction. NSG mice transplanted with these BCP-ALL cells were monitored for survival. Compared to mice transplanted with leukemia cells expressing original ST6Gal1 levels, increased ST6Gal1 expression was associated with significantly reduced survival. A cohort of mice was also treated for 7 weeks with vincristine chemotherapy to induce remission and then allowed to relapse. Upon vincristine discontinuation, relapse was detected in both groups, but mice transplanted with ST6Gal1 overexpressing BCP-ALL cells had an increased leukemia burden and shorter survival than controls. The BCP-ALL cells with higher ST6Gal1 were more resistant to long-term vincristine treatment in an ex vivo tissue co-culture model with OP9 bone marrow stromal cells. Gene expression analysis using RNA-seq showed a surprisingly large number of genes with significantly differential expression, of which approximately 60% increased mRNAs, in the ST6Gal1 overexpressing BCP-ALL cells. Pathways significantly downregulated included those involved in immune cell migration. However, ST6Gal1 knockdown cells also showed increased insensitivity to chemotherapy. Our combined results point to a context-dependent effect of ST6Gal1 expression on BCP-ALL cells, which is discussed within the framework of its activity as an enzyme with many N-linked glycoprotein substrates. |
format | Online Article Text |
id | pubmed-8967368 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-89673682022-03-31 Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia Zhang, Mingfeng Qi, Tong Yang, Lu Kolarich, Daniel Heisterkamp, Nora Front Oncol Oncology Normal early human B-cell development from lymphoid progenitors in the bone marrow depends on instructions from elements in that microenvironment that include stromal cells and factors secreted by these cells including the extracellular matrix. Glycosylation is thought to play a key role in such interactions. The sialyltransferase ST6Gal1, with high expression in specific hematopoietic cell types, is the only enzyme thought to catalyze the terminal addition of sialic acids in an α2-6-linkage to galactose on N-glycans in such cells. Expression of ST6Gal1 increases as B cells undergo normal B-lineage differentiation. B-cell precursor acute lymphoblastic leukemias (BCP-ALLs) with differentiation arrest at various stages of early B-cell development have widely different expression levels of ST6GAL1 at diagnosis, with high ST6Gal1 in some but not in other relapses. We analyzed the consequences of increasing ST6Gal1 expression in a diagnosis sample using lentiviral transduction. NSG mice transplanted with these BCP-ALL cells were monitored for survival. Compared to mice transplanted with leukemia cells expressing original ST6Gal1 levels, increased ST6Gal1 expression was associated with significantly reduced survival. A cohort of mice was also treated for 7 weeks with vincristine chemotherapy to induce remission and then allowed to relapse. Upon vincristine discontinuation, relapse was detected in both groups, but mice transplanted with ST6Gal1 overexpressing BCP-ALL cells had an increased leukemia burden and shorter survival than controls. The BCP-ALL cells with higher ST6Gal1 were more resistant to long-term vincristine treatment in an ex vivo tissue co-culture model with OP9 bone marrow stromal cells. Gene expression analysis using RNA-seq showed a surprisingly large number of genes with significantly differential expression, of which approximately 60% increased mRNAs, in the ST6Gal1 overexpressing BCP-ALL cells. Pathways significantly downregulated included those involved in immune cell migration. However, ST6Gal1 knockdown cells also showed increased insensitivity to chemotherapy. Our combined results point to a context-dependent effect of ST6Gal1 expression on BCP-ALL cells, which is discussed within the framework of its activity as an enzyme with many N-linked glycoprotein substrates. Frontiers Media S.A. 2022-03-16 /pmc/articles/PMC8967368/ /pubmed/35371997 http://dx.doi.org/10.3389/fonc.2022.828041 Text en Copyright © 2022 Zhang, Qi, Yang, Kolarich and Heisterkamp https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Oncology Zhang, Mingfeng Qi, Tong Yang, Lu Kolarich, Daniel Heisterkamp, Nora Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia |
title | Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia |
title_full | Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia |
title_fullStr | Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia |
title_full_unstemmed | Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia |
title_short | Multi-Faceted Effects of ST6Gal1 Expression on Precursor B-Lineage Acute Lymphoblastic Leukemia |
title_sort | multi-faceted effects of st6gal1 expression on precursor b-lineage acute lymphoblastic leukemia |
topic | Oncology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8967368/ https://www.ncbi.nlm.nih.gov/pubmed/35371997 http://dx.doi.org/10.3389/fonc.2022.828041 |
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