Elevated mitochondrial DNA copy numbers in pediatric acute lymphoblastic leukemia: A potential biomarker for predicting inferior survival

Jain, Ayushi; Bakhshi, Sameer; Thakkar, Himani; Gerards, Mike; Singh, Archna

doi:10.1002/pbc.26874

Cited by 13 publications

(9 citation statements)

References 31 publications

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“…Several reports have shown that an increase of mtDNA copy number, an indicator of mitochondrial biogenesis, is associated with poor prognosis in colorectal cancer, gastric cancer and lymphoblastic leukemia glioma (45)(46)(47). The present study found that the mtDNA copy number in SKOV3/DDP cells gradually increased with cisplatin exposure duration, whereas the copy number in SKOV3 cells decreased ( Fig.…”

Section: Discussionsupporting

confidence: 63%

PGC1α promotes cisplatin resistance in human ovarian carcinoma cells through upregulation of mitochondrial biogenesis

et al. 2018

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The induction of lesions in nuclear and mitochondrial DNA by cisplatin is only a small component of its cytostatic/cytotoxic activity. The signaling pathway network in the nucleus and cytoplasm may contribute to chemotherapeutic resistance. Peroxisome proliferator-activated receptor-coactivator 1α (PGC1α)-mediated mitochondrial biogenesis regulates mitochondrial structural and the functional adaptive response against chemotherapeutic stress, and may be a therapeutic target. However, this regulatory network is complex and depends upon tumor types and environments, which require further investigation. Our previous study found that cisplatin-resistant ovarian epithelial carcinoma was more dependent on mitochondrial aerobic oxidation to support their growth, suggesting the association between mitochondrial function and chemotherapeutic resistance. In the present study, it was demonstrated that the expression of PGC1α and level of mitochondrial biogenesis were higher in cisplatin-resistant SKOV3/DDP cells compared with cisplatin-sensitive SKOV3 cells. Furthermore, SKOV3/DDP cells upregulated the expression of PGC1α and maintained mitochondrial structural and functional integrity through mitochondrial biogenesis under cisplatin stress. Inhibiting the expression of PGC1α using short hairpin RNA led to the downregulation of mitochondrial biogenesis and high levels of apoptosis in the SKOV3/DDP cells, and cisplatin resistance was reversed in the PGC1α-deficient SKOV3/DDP cells. Collectively, the present study provided evidence that cisplatin stimulated the expression of PGC1α and the upregulation of mitochondrial biogenesis through PGC1α, promoting cell viability and inhibiting apoptosis in response to cisplatin treatment, thus triggering cisplatin resistance in ovarian cancer cells.

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Section: Discussionsupporting

confidence: 63%

PGC1α promotes cisplatin resistance in human ovarian carcinoma cells through upregulation of mitochondrial biogenesis

et al. 2018

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“…In pediatric AML cells increased TFAM and POLG expression have been described along with increased mtDNA copy number, reversible with PGC-1α inhibition [35]. In addition, mtDNA copy number was found to be increased in pediatric acute lymphoblastic leukemia (ALL) samples, which significantly decreased after treatment [37]. Additionally, there is growing evidence that mtDNA polymorphisms can influence drug response in various cancers [38].…”

Section: Mtdna Changes In Cancermentioning

confidence: 99%

Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

Czegle

Gray

Wang³

et al. 2021

Life

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Hematologic malignancies are known to be associated with numerous cytogenetic and molecular genetic changes. In addition to morphology, immunophenotype, cytochemistry and clinical characteristics, these genetic alterations are typically required to diagnose myeloid, lymphoid, and plasma cell neoplasms. According to the current World Health Organization (WHO) Classification of Tumors of Hematopoietic and Lymphoid Tissues, numerous genetic changes are highlighted, often defining a distinct subtype of a disease, or providing prognostic information. This review highlights how these molecular changes can alter mitochondrial bioenergetics, cell death pathways, mitochondrial dynamics and potentially be related to mitochondrial genetic changes. A better understanding of these processes emphasizes potential novel therapies.

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“…Each human cell has hundreds and thousands of mitochondria with each carrying a variable number of mitochondrial DNA (mtDNA) copies (Ju et al 2014 ; Wallace 2012 ). Findings from our lab have previously demonstrated a higher mtDNA copy number in lymphoblasts of pediatric ALL patients as compared to mononuclear cells of healthy controls (Jain et al 2018 ). MtDNA replication and the transcription and translation of mtDNA encoded genes form an integral part of mitochondrial biogenesis.…”

Section: Introductionmentioning

confidence: 77%

Ultrastructural changes in cristae of lymphoblasts in acute lymphoblastic leukemia parallel alterations in biogenesis markers

et al. 2021

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We explored the link between mitochondrial biogenesis and mitochondrial morphology using transmission electron microscopy (TEM) in lymphoblasts of pediatric acute lymphoblastic leukemia (ALL) patients and compared these characteristics between tumors and control samples. Gene expression of mitochondrial biogenesis markers was analysed in 23 ALL patients and 18 controls and TEM for morphology analysis was done in 15 ALL patients and 9 healthy controls. The area occupied by mitochondria per cell and the cristae cross-sectional area was observed to be significantly higher in patients than in controls (p-value = 0.0468 and p-value< 0.0001, respectively). The mtDNA copy numbers, TFAM, POLG, and c-myc gene expression were significantly higher in ALL patients than controls (all p-values< 0.01). Gene Expression of PGC-1α was higher in tumor samples. The analysis of the correlation between PGC-1α expression and morphology parameters i.e., both M/C ratio and cristae cross-sectional area revealed a positive trend (r = 0.3, p = 0.1). The increased area occupied by mitochondria and increased cristae area support the occurrence of cristae remodelling in ALL. These changes might reflect alterations in cristae dynamics to support the metabolic state of the cells by forming a more condensed network. Ultrastructural imaging can be useful for affirming changes occurring at a subcellular organellar level.

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Elevated mitochondrial DNA copy numbers in pediatric acute lymphoblastic leukemia: A potential biomarker for predicting inferior survival

Abstract: Significant decreases in mitochondrial DNA copy number with therapy indicates that copy number could be evaluated as a potential marker for therapeutic efficacy and a higher mitochondrial DNA copy number could be a poor prognostic marker.

Cited by 13 publications

References 31 publications

PGC1α promotes cisplatin resistance in human ovarian carcinoma cells through upregulation of mitochondrial biogenesis

PGC1α promotes cisplatin resistance in human ovarian carcinoma cells through upregulation of mitochondrial biogenesis

Mitochondria and Their Relationship with Common Genetic Abnormalities in Hematologic Malignancies

Ultrastructural changes in cristae of lymphoblasts in acute lymphoblastic leukemia parallel alterations in biogenesis markers

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