Sugarcoating matters: Deciphering the effects of aberrant receptor N-glycosylation on oncogenesis and drug resistance in acute myeloid leukemia

During my post-doctoral studies, I have shown that sugarcoating of proteins, “N-glycosylation” specifically, is essential for the development and a potential therapeutic target in the blood cancer myeloproliferative neoplasms.

Here, I show that differential expression of three enzymes that are key to protein sugar coating are strong novel prognostic factors in the blood cancer acute myeloid leukemia (AML). Specifically, these enzymes remove or add glucose molecules of the N-glycan sugar tree.

Removal of the outer glucoses is essential for retaining N-glycoproteins within the endoplasmic reticulum (ER) and unprocessed N-glycans contain a high number of mannose sugars.

I hypothesize that unprocessed N-glycoproteins such as growth receptors and drug removal pumps escape the ER and are expressed on the cell surface at a higher level due to abnormal expression of genes implicated in sugar coating (ALG10B, MOGS and PRKCSH). This in turn contributes to AML development and poor outcome.

To proof my hypothesis, I will decipher the role of key enzymes in N-glycan glucose addition and removal to myeloid oncogenesis (aim 1A) and drug resistance (aim 1B) using colony forming unit assays and cell lines that express ALG10B or lack MOGS/PRKCSH (CRISPR-Cas9 knockout).

Additionally, I will assess mannose abundance and targetability on primary AML versus healthy control bone marrow samples (aim 2A), and map N-glycan structures using recently developed high-throughput mass spectrometry and analyses techniques (aim 2B).

I will correlate structural N-glycan profiles with expression of N-glycan processing enzymes assessed through RNA-sequencing to create a full picture of N-glycosylation aberrancies in AML.

This study will decipher the molecular mechanisms underlying aberrant N-glycosylation in AML and provide anchor points for novel AML therapies.

This is important, because the current 5-year overall survival rate of AML is only ~30% so therapy improvements are highly warranted.