Somatic mitochondrial DNA mutations are a source of heterogeneity among primary leukemic cells

Somatic mitochondrial DNA (mtDNA) mutations are prevalent in tumors, yet defining their biological significance remains challenging due to the intricate interplay between selective pressure, heteroplasmy, and cell state. Utilizing bulk whole-genome sequencing data from matched tumor and normal samples from two cohorts of pediatric cancer patients, we uncover differences in the accumulation of synonymous and nonsynonymous mtDNA mutations in pediatric leukemias, indicating distinct selective pressures. By integrating single-cell sequencing (SCS) with mathematical modeling and network-based systems biology approaches, we identify a correlation between the extent of cell-state changes associated with tumor-enriched mtDNA mutations and the selective pressures shaping their distribution among individual leukemic cells. Our findings also reveal an association between specific heteroplasmic mtDNA mutations and cellular responses that may contribute to functional heterogeneity among leukemic cells and influence their fitness. This study highlights the potential of SCS strategies for distinguishing between pathogenic and passenger somatic mtDNA mutations in cancer. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=197 SRC="FIGDIR/small/24314381v1_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@1cf81dforg.highwire.dtl.DTLVardef@57596dorg.highwire.dtl.DTLVardef@b019d9org.highwire.dtl.DTLVardef@171033f_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LINonsynonymous and synonymous mtDNA SNVs are subject to different selective pressures among pediatric leukemias C_LIO_LIThe distribution of mtDNA SNV VAFs among individual leukemic cells can provide evidence for selective pressure C_LIO_LIThe impact of mtDNA SNVs on gene expression is correlated with selective pressure C_LIO_LISomatic mtDNA SNVs associated with cell state changes are a source of heterogeneity among leukemic cells C_LI