Targeting mitochondrial RNA polymerase in acute myeloid leukemia.
Acute myeloid leukemia (AML) cells have high oxidative phosphorylation and mitochondrial mass and low respiratory chain spare reserve capacity. We reasoned that targeting the mitochondrial RNA polymerase (POLRMT), which indirectly controls oxidative phosphorylation, represents a therapeutic strategy for AML. POLRMT-knockdown OCI-AML2 cells exhibited decreased mitochondrial gene expression, decreased levels of assembled complex I, decreased levels of mitochondrially-encoded Cox-II and decreased oxidative phosphorylation. POLRMT-knockdown cells exhibited an increase in complex II of the electron transport chain, a complex comprised entirely of subunits encoded by nuclear genes, and POLRMT-knockdown cells were resistant to a complex II inhibitor theonyltrifluoroacetone. POLRMT-knockdown cells showed a prominent increase in cell death. Treatment of OCI-AML2 cells with 10-50 µM 2-C-methyladenosine (2-CM), a chain terminator of mitochondrial transcription, reduced mitochondrial gene expression and oxidative phosphorylation, and increased cell death in a concentration-dependent manner. Treatment of normal human hematopoietic cells with 2-CM at concentrations of up to 100 µMdid not alter clonogenic growth, suggesting a therapeutic window. In an OCI-AML2 xenograft model, treatment with 2-CM (70 mg/kg, i.p., daily) decreased the volume and mass of tumours to half that of vehicle controls. 2-CM did not cause toxicity to major organs. Overall, our results in a preclinical model contribute to the functional validation of the utility of targeting the mitochondrial RNA polymerase as a therapeutic strategy for AML.
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Fernando N
FN
Bralha
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Sanduni U
SU
Liyanage
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Rose
R
Hurren
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Xiaoming
X
Wang
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Meong Hi
MH
Son
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Thomas A
TA
Fung
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Francine B
FB
Chingcuanco
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Aveline Y W
AY
Tung
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.|Department of Psychiatry, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.|Centre for Addiction and Mental Health, Toronto, Ontario, Canada.
Ana C
AC
Andreazza
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Pamela
P
Psarianos
Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Aaron D
AD
Schimmer
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Leonardo
L
Salmena
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada.
Rebecca R
RR
Laposa
D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D012321:DNA-Directed RNA Polymerases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D042967:Electron Transport Complex I / Q000235:genetics / Q000378:metabolism; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D008297:Male; D016513:Mice, SCID; D008928:Mitochondria / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D058990:Molecular Targeted Therapy; D010085:Oxidative Phosphorylation; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden / Q000187:drug effects; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
C569537:2'-C-methyladenosine; D000970:Antineoplastic Agents; C117108:cytochrome C oxidase subunit II; D003576:Electron Transport Complex IV; D012321:DNA-Directed RNA Polymerases; C519567:POLRMT protein, human; D042967:Electron Transport Complex I; D000241:Adenosine
acute myeloid leukemia; electron transport chain; mitochondria; mitochondrial RNA polymerase; oxidative phosphorylation