Profiling of Metabolic Differences between Hematopoietic Stem Cells and Acute/Chronic Myeloid Leukemia

Abstract

Although many studies have been conducted on leukemia, only a few have analyzed the metabolomic profiles of various leukemic cells. In this study, the metabolomes of THP-1, U937, KG-1 (acute myelogenous leukemia, AML), K562 (chronic myelogenous leukemia, CML), and cord blood-derived CD34-positive hematopoietic stem cells (HSC) were analyzed using gas chromatography-mass spectrometry, and specific metabolic alterations were found using multivariate statistical analysis. Compared to HSCs, leukemia cell metabolomes were found to have significant alterations, among which three were related to amino acids, three to sugars, and five to fatty acids. Compared to CML, four metabolomes were observed specifically in AML. Given that overall more metabolites are present in leukemia cells than in HSCs, we observed that the activation of glycolysis and oxidative phosphorylation (OXPHOS) metabolism facilitated the incidence of leukemia and the proliferation of leukemic cells. Analysis of metabolome profiles specifically present in HSCs and leukemia cells greatly increases our basic understanding of cellular metabolic characteristics, which is valuable fundamental knowledge for developing novel anticancer drugs targeting leukemia metabolism.

Keywords: K562; KG-1; THP-1; U937; acute myelogenous leukemia; chronic myelogenous leukemia; hematopoietic stem cells; metabolome.

Figure 1

(A) Principal component analysis (PCA) and (B) partial least squares-discriminant analysis (PLS-DA) score plot derived from the GC-TOF-MS datasets of four different leukemia cell lines and one hematopoietic stem cells (HSC) line. (●, HSC; ●, THP-1; ●, KG-1; ●, U-937; ●, K562).

Figure 2

Heatmap showing hierarchical clustering analysis of metabolomic changes among four different leukemia cell lines and a normal hematopoietic stem cell (HSC) line. Metabolites were selected by VIP value > 0.7 and p value < 0.05. The rows display the metabolites, and the columns represent the cell lines. The colored squares (blue-to-red) represent fold changes normalized by averaging each metabolite of four different leukemia cells and a normal HSC line. The color scheme is as follows: lower limit value, −3.17 (green); middle limit value, −0.18 (black); upper limit value, 2.73 (red).

Figure 3

Constructed metabolic pathway showing relative metabolite contents for four different leukemia cell lines and a normal hematopoietic stem cell (HSC) line. The pathway was modified from the Kyoto Encyclopedia of Genes and Genomes (KEGG) database (http://www.genome.jp/kegg/). The colored squares (blue-to-red) represent relative metabolite abundance in the five cell lines.