Targeting mitochondrial RNA polymerase in acute myeloid leukemia

Abstract

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.

Undermining ribosomal RNA transcription in both the nucleolus and mitochondrion: an offbeat approach to target MYC-driven cancer

“…Specifically, there are several ribonucleosides analogues, originally developed for antiviral therapy, which are substrates and inhibitors of human mitochondrial RNA polymerase (POLRMT) [ 33 ], and can be repurposed for cancer therapy. In preclinical studies the 2-C-methyladenosine ribonucleoside (2’-C-MeA) was shown to reduce mitochondrial gene expression and increase cell death in acute myelogenous leukemia (AML), while treatment of normal human hematopoietic cells did not alter clonogenic growth [ 27 ]. Due to the ancestral relationship between bacteria and mitochondria, several classes of antibiotics, including tetracyclines (e.g.…”

“…Inhibition of mitochondrial ribogenesis is also a promising anti-cancer approach [ 25 , 26 ]. Mitoribogenesis can be hindered by drugs targeting POLRMT-mediated mt-rRNA transcription, like 2'C-Methyl-Adenosine (2’-C-MeA), as recently reported in acute myelogenous leukemia studies [ 27 ]. Moreover, due to the conservation between bacteria and mitochondria, antibiotics inhibiting bacterial protein synthesis (e.g.…”

An Adaptable High-Throughput Technology Enabling the Identification of Specific Transcription Modulators

“…Recent reports suggest that inhibition of mitochondrial gene expression may be of therapeutic value in the treatment of certain forms of cancer (e.g., acute myeloid leukemia). [16][17] Based on the obtained results and chemical evaluation, our validated inhibitors therefore provide promising starting points for a follow-up medicinal chemistry optimization program to generate druglike leads that are suitable for further development.…”

“…16 Furthermore, a 2-C-methyladenosine (2-CM), which functions as a chain terminator of mitochondrial transcription, was shown to decrease acute myeloid leukemia cell growth in a mouse xenograft model. 17 The inhibitors identified here may be useful in further studies for effects on those specific forms of drug-resistant cancers, including lymphomas and Varying concentrations of analogs were added, as indicated in the figure. All reactions contained uridine triphosphate (UTP) (200 µM) and α-32 P guanosine triphosphate (GTP) (see Materials and Methods for details).…”

Mitochondrial Chemical Biology: New Probes Elucidate the Secrets of the Powerhouse of the Cell

“…Discovery of this compound was particularly notable, as mitochondrial proteases represent a class of enzymes for which few specific inhibitors had previously been available (Cole et al, 2015). Another study characterized the activity of 2-C-methyladenosine, a commonly used antiviral agent, as a specific inhibitor of POLRMT, the mitochondrial RNA polymerase (Bralha et al, 2015).…”