Germline Mitochondrial DNA Mutations As a Novel First Event in Childhood Myelodysplastic Syndrome

Mutations in the mitochondrial DNA (mtDNA) have been found in 50–60% of adult MDS patients, with an increasing frequency with rising age and ahigher incidence in more advanced MDS. In general, cells contain different amounts of mitochondria which can simultaneously harbour wildtype and mutated mtDNA. Co-existence of normal and mutant mtDNA is referred to as heteroplasmy, whereas the existence of only mutated mtDNA is called homoplasmy. As yet no information is available on the role of mtDNA mutations in pediatric MDS. We recently identified a family with (germline) mtDNA mutations and childhood MDS. We hypothesized that mtDNA mutations, catalyzed by ATP deficiency, reflect the genetic instability of the stem cells that facilitates that the development of MDS clone initiation and subsequent clonal evolution to acute myeloid leukemia triggered by type I and II events.

Based on our findings in the above mentioned cases we analyzed the role of mtDNA mutations in the index family, in combination with studying oxidative phosphorylation, as well as in an extended cohort of 19 childhood MDS patients, including sporadic primary, therapy-related and familial MDS, using Mito-Chip (Affymetrix) and direct sequencing validation approach. To investigate whether the mutations were germline or somatic, in a subset of patients, germline mtDNA mutation analysis was performed.

In 14/19 of the pediatric MDS patients non-recurrent mtDNA mutations were found. Mt-mutational status was not correlated with the different WHO subgroups of childhood MDS. Heteroplasmic mutations were only found as somatic events, whereas. germline mutated cases were solely homoplasmic.

We describe the first family in which germline mtDNA mutations trigger the devlopment of MDS, and show for the first time, that also in sporadic MDS cases, germline homoplasmic mutations may genetically predispose for developping childhood proliferative myeloid disease.

No relevant conflicts of interest to declare.