Blood Res.  2018 Sep;53(3):240-249. 10.5045/br.2018.53.3.240.

Spectrum of mitochondrial genome instability and implication of mitochondrial haplogroups in Korean patients with acute myeloid leukemia

• Kim HR
• Kang MG
• Lee YE
• Na BR
• Noh MS
• Yang SH
• Shin JH
• Shin MG

• KMID: 2429325
• DOI: http://doi.org/10.5045/br.2018.53.3.240

Abstract

BACKGROUND
Mitochondrial DNA (mtDNA) mutations may regulate the progression and chemosensitivity of leukemia. Few studies regarding mitochondrial aberrations and haplogroups in acute myeloid leukemia (AML) and their clinical impacts have been reported. Therefore, we focused on the mtDNA length heteroplasmies minisatellite instability (MSI), copy number alterations, and distribution of mitochondrial haplogroups in Korean patients with AML.
METHODS
This study investigated 74 adult patients with AML and 70 controls to evaluate mtDNA sequence alterations, MSI, mtDNA copy number, haplogroups, and their clinical implications. The hypervariable (HV) control regions (HV1 and HV2), tRNA(leu1)gene, and cytochrome b gene of mtDNA were analyzed. Two mtDNA minisatellite markers, 16189 poly-C (¹â¶¹â¸â´CCCCCTCCCC¹â¶¹â¹³, 5CT4C) and 303 poly-C (³â°³CCCCCCCTCCCCC³¹âµ, 7CT5C), were used to examine the mtDNA MSI.
RESULTS
In AML, most mtDNA sequence variants were single nucleotide substitutions, but there were no significant differences compared to those in controls. The number of mtMSI patterns increased in AML. The mean mtDNA copy number of AML patients increased approximately 9-fold compared to that of controls (P < 0.0001). Haplogroup D4 was found in AML with a higher frequency compared to that in controls (31.0% vs. 15.7%, P=0.046). None of the aforementioned factors showed significant impacts on the outcomes.
CONCLUSION
AML cells disclosed more heterogeneous patterns with the mtMSI markers and had increased mtDNA copy numbers. These findings implicate mitochondrial genome instability in primary AML cells. Therefore, mtDNA haplogroup D4 might be associated with AML risk among Koreans.

Keyword

AML; Mitochondrial genome; Instability; Haplogroup; Outcome

MeSH Terms

Adult
Cytochromes b
DNA, Mitochondrial
Genome, Mitochondrial*
Humans
Leukemia
Leukemia, Myeloid, Acute*
Minisatellite Repeats
Cytochromes b
DNA, Mitochondrial

Figure

• 

  Fig. 1 Representative sequencing chromatograms revealing mtDNA mutations in tRNAleu1 gene (AML No.112 patient) and CYTB gene (AML No.50 patient) as nonsynonymous mutations. (A) mtDNA tRNAleu1 gene mutation-affected amino acid change (Ala→Thr) for AML patient No.112. (B) mtDNA CYTB gene mutation-affected amino acid change (Ala→Thr) for AML patient No.50.

• 

  Fig. 2 Gene scan analysis of poly C-stretch region at nucleotide position (np) 303–315, 16184–16193, and 514–515(CA)5 repeats. (A) The mtDNA D-loop HV2 (303 poly-C) region. Capillary electropherogram of the np 303 poly-C region from AML patient No.123 showed 9CT6C as a C insertion type. (B) The mtDNA D-loop HV1 (16189 poly-C) region. Capillary electropherogram of np 16184–16193 poly-C region from samples of AML No.29 patient also disclosed the profile of several mtDNA types (heteroplasmic mutations). (C) The mtDNA D-loop HV2 514–515(CA)5 repeats region. Gene scan analysis of CA repeats starting at np 514 (AML No.27 patient) also disclosed heteroplasmic mutations, which suggest the coexistence of wildtype and mutant mtDNA in the same patient.

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