Mitochondrial oxidative phosphorylation is dispensable for survival of CD34+ chronic myeloid leukemia stem and progenitor cells

Abstract

Chronic myeloid leukemia (CML) are initiated and sustained by self-renewing malignant CD34+ stem cells. Extensive efforts have been made to reveal the metabolic signature of the leukemia stem/progenitor cells in genomic, transcriptomic, and metabolomic studies. However, very little proteomic investigation has been conducted and the mechanism regarding at what level the metabolic program was rewired remains poorly understood. Here, using label-free quantitative proteomic profiling, we compared the signature of CD34+ stem/progenitor cells collected from CML individuals with that of healthy donors and observed significant changes in the abundance of enzymes associated with aerobic central carbonate metabolic pathways. Specifically, CML stem/progenitor cells expressed increased tricarboxylic acid cycle (TCA) with decreased glycolytic proteins, accompanying by increased oxidative phosphorylation (OXPHOS) and decreased glycolysis activity. Administration of the well-known OXPHOS inhibitor metformin eradicated CML stem/progenitor cells and re-sensitized CD34+ CML cells to imatinib in vitro and in patient-derived tumor xenograft murine model. However, different from normal CD34+ cells, the abundance and activity of OXPHOS protein were both unexpectedly elevated with endoplasmic reticulum stress induced by metformin in CML CD34+ cells. The four major aberrantly expressed protein sets, in contrast, were downregulated by metformin in CML CD34+ cells. These data challenged the dependency of OXPHOS for CML CD34+ cell survival and underlined the novel mechanism of metformin. More importantly, it suggested a strong rationale for the use of tyrosine kinase inhibitors in combination with metformin in treating CML.

Antileukemic potential of methylated indolequinone MAC681 through immunogenic necroptosis and PARP1 degradation

“…document SD1D-E). As previously reported, these results suggest that primary CML stem and progenitor cells of chronic phase CML patients present an aberrant proliferation with an increased metabolism to sustain high energetic demands [34]. Interestingly, pathways in DNA repair and disease, including DNA repair defects, were highly represented in both datasets, including diseases of mismatch repair and double-strand break repair linked to BRCA1/2 loss of function (Fig.…”

Properties of Leukemic Stem Cells in Regulating Drug Resistance in Acute and Chronic Myeloid Leukemias

“…Metabolic analysis of stem-cell enriched CD34 + and CD34 + CD38 − and differentiated CD34 − cells from CML patients has also indicated that CML LSCs require upregulated oxidative metabolism for their survival [ 204 ]. Nonetheless, a recent study challenged this notion, claiming that OXPHOS was also upregulated, as opposed to being downregulated, in metformin-mediated killing of CML stem and progenitor cells, suggesting the dispensability of OXPHOS in CML stem and progenitor cell survival [ 205 ]. Of note for this particular study, the potentially pleiotropic and uncharacterized effects of metformin may play a role in yielding such an interpretation.…”

Metformin exerts antileukemic effects by modulating lactate metabolism and overcomes imatinib resistance in chronic myelogenous leukemia

“…Metformin is a widely used antiglycemic drug for the treatment of type 2 diabetes. Preliminary studies have shown that metformin exhibits antileukemic properties [16][17][18][19]. However, the molecular mechanisms by which metformin elicits its antileukemic effects remain elusive [20].…”