Novel non‐neutral mitochondrial DNA mutations found in childhood acute lymphoblastic leukemia

Abstract

Mitochondria produce adenosine triphosphate (ATP) for energy requirements via the mitochondrial oxidative phosphorylation (OXPHOS) system. One of the hallmarks of cancer is the energy shift toward glycolysis. Low OXPHOS activity and increased glycolysis are associated with aggressive types of cancer. Mitochondria have their own genome (mitochondrial DNA [mtDNA]) encoding for 13 essential subunits of the OXPHOS enzyme complexes. We studied mtDNA in childhood acute lymphoblastic leukemia (ALL) to detect potential pathogenic mutations in OXPHOS complexes. The whole mtDNA from blood and bone marrow samples at diagnosis and follow-up from 36 ALL patients were analyzed. Novel or previously described pathogenic mtDNA mutations were identified in 8 out of 36 patients. Six out of these 8 patients had died from ALL. Five out of 36 patients had an identified poor prognosis genetic marker, and 4 of these patients had mtDNA mutations. Missense or nonsense mtDNA mutations were detected in the genes encoding subunits of OXPHOS complexes, as follows: MT-ND1, MT-ND2, MT-ND4L and MT-ND6 of complex I; MT-CO3 of complex IV; and MT-ATP6 and MT-ATP8 of complex V. We discovered mtDNA mutations in childhood ALL supporting the hypothesis that non-neutral variants in mtDNA affecting the OXPHOS function may be related to leukemic clones.

Whole mitochondrial genome sequencing highlights mitochondrial impact in gastric cancer

“…Such tumor-exclusive variants were distributed in 13 genes, of which three (MT- ATP8 , MT- ND4L and MT- TG ) were only observed in this group. Only a few studies have reported variants in MT- ATP8 31,32 and MT- ND4L 31,33–35 in different types of cancer and none was in gastric cancer. No studies were found associating variants in MT- TG to cancer.…”

Insights on the Interplay between Cells Metabolism and Signaling: A Therapeutic Perspective in Pediatric Acute Leukemias

“…In 8 out of 36 patients, missense or nonsense mutations in mtDNA (components of ETC-Complex I, Complex IV and the ATP synthase) were found, and 6 out these 8 patients died from ALL. Within the whole group, there was a correlation between a poor prognosis at diagnosis due to genetic markers and a mutated mtDNA pattern [31].…”

Metabolic reprogramming in childhood acute lymphoblastic leukemia

“…Such mtDNA mutations are also described in patients with cALL as shown by the detection of 73 nonneutral mutations in 36 patients 13,14 . The affected genes code for components of the ETC—Complex I (MT‐ND1, MT‐ND2, MT‐ND4L, and MT‐ND6), Complex IV (MT‐CO3), and the ATP synthase (MT‐ATP8) 14 . Even if functional data on these SNPs are not provided, such mutations are likely capable of altering the activity of the ETC.…”

“…Mutations in mitochondrial DNA (mtDNA) genes encoding components of oxidative phosphorylation (OxPhos) are present in a number of malignancies 12 . Such mtDNA mutations are also described in patients with cALL as shown by the detection of 73 nonneutral mutations in 36 patients 13,14 . The affected genes code for components of the ETC—Complex I (MT‐ND1, MT‐ND2, MT‐ND4L, and MT‐ND6), Complex IV (MT‐CO3), and the ATP synthase (MT‐ATP8) 14 .…”