Open AccessGlycoproteome remodeling in MLL-rearranged B-cell precursor acute lymphoblastic leukemia
Author(s) -
Tiago Oliveira,
Mingfeng Zhang,
Eun Ji Joo,
Hisham AbdelAzim,
Chun-Wei Chen,
Lu Yang,
Chih-Hsing Chou,
Xi Qin,
Jianjun Chen,
Kathirvel Alagesan,
Andreia Almeida,
Francis Jacob,
Nicolle H. Packer,
Mark von Itzstein,
Nora Heisterkamp,
Daniel Kolarich
Publication year - 2021
Publication title -
theranostics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.689
H-Index - 97
ISSN - 1838-7640
DOI - 10.7150/thno.65398
Subject(s) - glycomics , proteomics , transcriptome , biology , computational biology , glycan , fucosylation , leukemia , cancer research , microbiology and biotechnology , biochemistry , gene , gene expression , glycoprotein , immunology
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) with mixed-lineage leukemia gene rearrangement (MLL-r) is a poor-prognosis subtype for which additional therapeutic targets are urgently needed. Currently no multi- omics data set for primary MLL r patient cells exists that integrates transcriptomics, proteomics and glycomics to gain an inclusive picture of theranostic targets. Methods: We have integrated transcriptomics, proteomics and glycomics to i) obtain the first inclusive picture of primary patient BCP-ALL cells and identify molecular signatures that distinguish leukemic from normal precursor B-cells and ii) better understand the benefits and limitations of the applied technologies to deliver deep molecular sequence data across major cellular biopolymers. Results: MLL-r cells feature an extensive remodeling of their glycocalyx, with increased levels of Core 2-type O-glycans and complex N-glycans as well as significant changes in sialylation and fucosylation. Notably, glycosaminoglycan remodeling from chondroitin sulfate to heparan sulfate was observed. A survival screen, to determine if glycan remodeling enzymes are redundant, identified MGAT1 and NGLY1, essential components of the N-glycosylation/degradation pathway, as highly relevant within this in vitro screening. OGT and OGA, unique enzymes that regulate intracellular O-GlcNAcylation, were also indispensable. Transcriptomics and proteomics further identified Fes and GALNT7-mediated glycosylation as possible therapeutic targets. While there is overall good correlation between transcriptomics and proteomics data, we demonstrate that a systematic combined multi- omics approach delivers important diagnostic information that is missed when applying a single omics technology. Conclusions: Apart from confirming well-known MLL-r BCP-ALL glycoprotein markers, our integrated multi- omics workflow discovered previously unidentified diagnostic/therapeutic protein targets.