Impaired mitochondrial gene transcription in myelodysplastic syndromes and acute myeloid leukemia with myelodysplasia-related changes

Abstract

Objective: To examine mitochondrial gene expression in hematopoietic progenitor cells of patients with myelodysplastic syndromes (MDS). Mitochondrial pathology in MDS is suggested by abnormal mitochondrial iron accumulation, increased apoptosis, and a high frequency of acquired mitochondrial DNA mutations in bone marrow cells.

Materials and methods: Mitochondrial gene expression was measured by real-time reverse transcription polymerase chain reaction in CD34(+) bone marrow cells from 37 patients with MDS (22 refractory cytopenia with multilineage dysplasia, 9 refractory anemia with excess of blasts [5-9% marrow blasts], 6 refractory anemia with excess of blasts [10-19% marrow blasts]), 14 cases of acute myeloid leukemia with myelodysplasia-related changes (acute myeloid leukemia-MDS), and 9 normal controls. Relative quantification was achieved by using specific plasmid standards and 18S ribosomal RNA. Genes were selected to represent the multi-enzyme complexes I to IV of the mitochondrial respiratory chain: nicotinamide adenine dinucleotide dehydrogenase subunit 3 (subunit of complex I), succinate dehydrogenase B (complex II), cytochrome B (complex III), and cytochrome-c-oxidase subunit I (complex IV).

Results: Expression of mitochondrial-encoded genes was significantly reduced in patients with MDS and acute myeloid leukemia-MDS compared to normal controls, while mitochondrial DNA copy number was increased rather than diminished. An age-related decrease in mitochondrial gene expression was observed in MDS patients as well as controls. However, this effect was less pronounced than the MDS-related effect. Besides an overall decrease in mitochondrial gene expression, MDS patients displayed a stochiometric imbalance of mitochondrial-encoded genes, assessed in relation to the nuclear-encoded succinate dehydrogenase B.

Conclusions: Our results show dysregulated mitochondrial gene expression that goes beyond a simple age-related effect and is compatible with the putative role of mitochondrial dysfunction in MDS pathophysiology. However, it remains unclear whether the problem arises from primary lesions in the mitochondria, i.e., mitochondrial DNA mutations, or as a result of changes in the cell nucleus.