A new look at ADAR1
SAN DIEGO—Though the role of RNA in cancer hasn't been thoroughly explored yet, some light has been shed on the impact of at least one enzyme: adenosine deaminase acting on RNA1, or ADAR1. ADAR1's role in the body is to edit microRNA sequences. When one microRNA segment is swapped for another, ADAR1 can change the system cells use to control which genes are turned off or on, and at which times. The enzyme is known to promote both cancer progression and resistance to treatment.
A team led by Dr. Catriona Jamieson, associate professor of medicine and chief of the Division of Regenerative Medicine at UC San Diego School of Medicine, explored the role ADAR1 plays in leukemia, specifically its impact on cancer stem cells. The study's results were published in Cell Stem Cell in a paper titled “ADAR1 Activation Drives Leukemia Stem Cell Self-Renewal by Impairing Let-7 Biogenesis.”
As noted in the paper's abstract, it is known that “Post-transcriptional adenosine- to-inosine RNA editing mediated by adenosine deaminase acting on RNA1 (ADAR1) promotes cancer progression and therapeutic resistance. However, ADAR1 editase-dependent mechanisms governing leukemia stem cell (LSC) generation have not been elucidated.”
The team worked with both human blast crisis chronic myeloid leukemia cells in the lab and mice transplanted with the same cells. They found that white blood cells with a leukemia-promoting gene mutation become more sensitive to signs of inflammation. That inflammatory response activates ADAR1, and in turn, hyper-ADAR1 editing slows down the microRNAs let-7, which increases cellular regeneration, turning white blood cell precursors into leukemia stem cells. These stem cells promote an aggressive form of leukemia that is resistant to therapy known as blast crisis.
“In this study, we showed that cancer stem cells co-opt a RNA editing system to clone themselves. What’s more, we found a method to dial it down,” said Jamieson, senior author of the study and deputy director of the Sanford Stem Cell Clinical Center at UC San Diego Health, director of the CIRM Alpha Stem Cell Clinic at UC San Diego School of Medicine and director of stem cell research at UC San Diego Moores Cancer Center. Jamieson added that “This is the first mechanistic link between pro-cancer inflammatory signals and RNA editing-driven reprogramming of precursor cells into leukemia stem cells.”
The team then discovered that by inhibiting ADAR1 with a small-molecule tool compound, 8-Aza, they could counter the enzyme's effect on leukemia stem cell self-renewal and restore let-7. In fact, self-renewal of blast crisis chronic myeloid leukemia cells was reduced by roughly 40 percent when treated with 8-Aza compared to untreated cells.
Specifically, “In a humanized BC CML mouse model, combined JAK2 and BCR-ABL1 inhibition prevents LSC self-renewal commensurate with ADAR1 downregulation. Lentiviral ADAR1 wild-type, but not an editing-defective ADAR1E912A mutant, induces self-renewal gene expression and impairs biogenesis of stem cell regulatory let-7 microRNAs,” as noted in the abstract.
This is not the first time ADAR1 has attracted interest for its impact in leukemia. In a 2013 article in Proceedings of the National Academy of Sciences, “whole- transcriptome sequencing of normal, chronic phase and serially transplantable blast crisis chronic myeloid leukemia (CML) progenitors revealed increased IFN-γ pathway gene expression in concert with BCR-ABL amplification, enhanced expression of the IFN-responsive ADAR1 p150 isoform and a propensity for increased adenosine-to-inosine RNA editing during CML progression. Lentiviral overexpression experiments demonstrate that ADAR1 p150 promotes expression of the myeloid transcription factor PU.1 and induces malignant reprogramming of myeloid progenitors. Moreover, enforced ADAR1 p150 expression was associated with production of a misspliced form of GSK3β implicated in LSC self-renewal. Finally, functional serial transplantation and shRNA studies demonstrate that ADAR1 knockdown impaired in-vivo self-renewal capacity of blast crisis CML progenitors.”
“Based on this research, we believe that detecting ADAR1 activity will be important for predicting cancer progression. In addition, inhibiting this enzyme represents a unique therapeutic vulnerability in cancer stem cells with active inflammatory signaling that may respond to pharmacologic inhibitors of inflammation sensitivity or selective ADAR1 inhibitors that are currently being developed,” Jamieson said.