Ordinarily, the enzymes APOBEC3C and ADAR1 help us fight off viruses. In the heat of battle, however, they can form a nefarious tag team that pushes preleukemia stem cells to become leukemia stem cells. Here, the “heat of battle” is usually inflammation. It may also refer to the dysregulation that occurs during space travel.
The successive blows landed by APOBEC3C and ADAR1 were observed by researchers at UC San Diego Health and the University of California San Diego School of Medicine. The researchers also found that they could block ADAR1 to prevent the formation of leukemia stem cells.
Details of the researchers’ work appeared January 26 in Cell Reports, in an article titled, “Inflammation-driven deaminase deregulation fuels human preleukemia stem cell evolution.” The phrase “deaminase dysregulation” refers to an increase in C-to-T mutational burden in preleukemia stem cells. This increase, which is driven by APOBEC3C, results in the proliferation of hematopoietic stem and progenitor cells. It is succeeded by ADAR1-induced A-to-I RNA hyper-editing.
To get a ringside seat during the precancer to cancer progression, the researchers used comparative whole-genome and whole-transcriptome sequencing analyses of preleukemia stem cells from myeloproliferative neoplasm patients.
Basically, the researchers collected blood stem cells and saliva samples donated by 54 patients with leukemia and 24 healthy control participants. When the researchers compared their sequencing data for the preleukemia stem cells and leukemia stem cells, they were surprised to discover an uptick in levels of both APOBEC3C and ADAR1 during the progression to leukemia stem cell.
Ordinarily, APOBEC3C helps restrict RNA virus replication, and ADAR1 edits RNA to modify gene expression. These are useful functions. But the researchers found that in response to inflammation, APOBEC3C can promote the proliferation of human preleukemia stem cells. This exploit sets the stage for ADAR1, which becomes overzealous in its editing, skewing gene expression in a way that supports leukemia stem cells.
When the researchers inhibited ADAR1 activation or silenced the gene in patient cells in the laboratory, they were able to prevent the formation of leukemia stem cells.
“Preleukemia stem cell (pre-LSC) evolution to acute myeloid leukemia stem cells (LSCs) is marked by STAT3 editing, STAT3β isoform switching, elevated phospho-STAT3, and increased ADAR1p150 expression, which can be prevented by JAK2/STAT3 inhibition with ruxolitinib or fedratinib or lentiviral ADAR1 shRNA knockdown,” the authors of the Cell Reports article wrote. “Conversely, lentiviral ADAR1p150 expression enhances pre-LSC replating and STAT3 splice isoform switching.” Fedratinib and ruxolitinib are existing medications myelofibrosis, a rare bone marrow cancer.
“APOBEC3C and ADAR1 are like the Bonnie and Clyde of precancer stem cells—they drive the cells into malignancy,” said Catriona Jamieson, MD, PhD, the study’s co-senior author. She is the Koman Family Presidential Endowed Chair in Cancer Research, deputy director of Moores Cancer Center, director of the Sanford Stem Cell Clinical Center, and director of the CIRM Alpha Stem Cell Clinic at UC San Diego Health.
Jamieson and colleagues are working to understand what pushes precancer stem cells to transform into cancer stem cells and are developing ways to stop that switch. Since stem cells can continually self-regenerate and differentiate into many different specialized cell types, they play an important role in our development and health. But there can also be a dark side—stem cells can sometimes become cancer stem cells, proliferating out of control and leading to blood cancers, such as leukemia and multiple myeloma. The self-renewing nature of cancer stem cells makes them particularly hard to eradicate, and they’re often the reason a blood cancer reoccurs.
Jamieson’s team has long studied ADAR1, an enzyme that edits a cell’s genetic material to control which genes are turned on or off at which times, and its role in leukemia stem cells. The team also previously found that high ADAR1 levels correlate with reduced survival rates for patients with multiple myeloma.
The roles played by APOBEC3C and ADAR1 in cancer stem cells are now the focus of Jamieson’s NASA-funded project to develop the first dedicated stem cell research laboratory within the International Space Station (ISS). That’s because the NASA Twins Study—a comprehensive biological comparison of identical twins Scott Kelly, who spent six months aboard the ISS, and Mark Kelly, who stayed on Earth—revealed an increase in inflammatory growth factors, immune dysregulation, and precancer mutations in Scott’s blood upon his return. These molecular changes, the perfect conditions to activate APOBEC3C and ADAR1, persisted for almost a year.
“Under the auspices of our NASA task order, we are now developing APOBEC3C and ADAR1 inhibitors as a risk-mitigation strategy for astronauts,” noted Jamieson. “[We hope to] predict and prevent precancer stem cell generation in low-Earth orbit and on deep space missions.”
The team is also interested in further exploring the link between viral infections and cancer. According to Jamieson, infection with viruses can trigger a flood of cytokines, molecules that help stimulate the body’s immune forces. As part of that response, ADAR1 is activated to help immune cells proliferate.
“We need APOBEC3C and ADAR to help us fight off viruses,” she explained. “So now we’re wondering—do these enzymes play a role in the immune response to COVID-19? And could there be a downside to that as well? Can the immune response to a viral infection later raise a person’s risk of precancer stem cell development and ultimately cancer stem cell generation, and can we intervene to prevent that?”
