# Glycolytic Enzymes Are Part of an Oncogenic Network in AML

## TL;DR

This study shows how abnormal activity of glycolytic enzymes in a leukemia cell line contributes to cancer growth and suggests new treatment strategies.

## Contribution

The study identifies a novel oncogenic network involving glycolytic enzymes and glucose metabolism in AML.

## Key findings

- Aberrant PFKL overexpression lowers glucose levels in AML cells.
- Reduced glucose activates IRF6 and developmental genes in OCI-M2 cells.
- PFKL and GPI are linked to an oncogenic network involving IRF6 and NKX2-4.

## Abstract

What are the main findings?
Aberrant PFKL overexpression reduces the intra-cellular glucose level in AML cell line OCI-M2.The reduced glucose level activates developmental gene activities including IRF6 and its downstream targets.

Aberrant PFKL overexpression reduces the intra-cellular glucose level in AML cell line OCI-M2.

The reduced glucose level activates developmental gene activities including IRF6 and its downstream targets.

What is the implication of the main finding?
Cell line OCI-M2 may serve as an in vitro model to establish glycolysis-targeted therapies in AML.

Cell line OCI-M2 may serve as an in vitro model to establish glycolysis-targeted therapies in AML.

Erythroid acute myeloid leukemia (AML) cell line OCI-M2 expresses a particular oncogenic network: IRF6, in concert with ETV2 and HEY1, aberrantly activates NKL homeobox gene NKX2-4, which in turn represses megakaryocytic lineage factor FLI1. Interestingly, in keratinocytes, IRF6 is able to bind glucose which promotes IRF6-dimerization and thus alters its binding site selection. Here, we used OCI-M2 as a model to investigate the role of glucose level and IRF6 in leukemogenesis. Treatment of OCI-M2 with high glucose or 2-deoxy-glucose resulted in the downregulation of IRF6 and NKX2-4, and the upregulation of FLI1, indicating that glucose-mediated dimerization of IRF6 altered its reported autoactivation. The screening of this cell line for genes encoding glycolytic enzymes identified aberrant overexpression of glucose-6-phosphate isomerase (GPI) and phosphofructokinase L (PFKL), which were targeted by genomic amplification and chromothripsis-like alterations, respectively. Furthermore, GPI was activated by NKX2-4 and ETV2, and PFKL by ETV2. Finally, siRNA-mediated downregulation of PFKL resulted in elevated glucose levels, suppressed expression of IRF6 and NKX2-4, and activated FLI1. Thus, we connected an oncogenic regulatory network with deregulated glycolytic enzymes and glucose metabolism, thereby establishing a new in vitro model to develop novel therapeutic avenues in AML subsets.