An international team, headed by researchers at the University of California, San Diego School of Medicine, has identified a key enzyme in the reprogramming process that promotes malignant stem cell cloning and the growth of chronic myeloid leukemia (CML), a cancer of the blood and marrow that experts say is increasing in prevalence.
The findings are published in the Dec. 24 online early edition of the Proceedings of the National Academy of Sciences (PNAS).
Despite the emergence of new therapies, such as tyrosine kinase inhibitors, CML and other leukemias remain problematic because some cancer stem cells avoid destruction and eventually regenerate themselves, a stem cell process known as self-renewal that can result in a return and spread (metastasis) of the disease.
In the PNAS paper, principal investigator Catriona H. M. Jamieson, MD, PhD, associate professor of medicine at UC San Diego, with colleagues in the United States, Canada and Italy, report that inflammation – long associated with the development of cancer – boosts activity of an enzyme called adenosine deaminase or ADAR1.
Expressed during embryogenesis to help blood cell development, ADAR1 subsequently turns off and is triggered by viral infections where it protects normal hematopoietic stem cells from attack. In leukemia stem cells, however, overexpression of ADAR1 enhances the missplicing of RNA, which leads to greater self-renewal and therapeutic resistance of malignant stem cells.
The findings build upon previous studies by Jamieson and others that elucidate the effects of RNA missplicing and instability. "People normally think about DNA instability in cancer, but in this case, it's how the RNA is edited by enzymes that really matters in terms of cancer stem cell generation and resistance to conventional therapy."
The described RNA editing process, which occurs in the context of human and other primate specific sequences, also underscores the importance of addressing inflammation as "an essential driver of cancer relapse and therapeutic resistance," Jamieson said. It also presents a new target for future therapies.
"ADAR1 is an enzyme that we may be able to specifically target with a small molecule inhibitor, an approach we have already used effectively with other inhibitors," said Jamieson. "If we can block the capacity of leukemia stem cells to use ADAR1, if we can knock down that pathway, maybe we can put stem cells back on the right track and stop malignant cloning."
CML is a cancer initiated by a mutant gene called BCR-ABL in blood forming stem cells that leads to an expansion of white blood cells and their precursors. It is typically slow-growing and often not diagnosed until its later stages when there can be a sudden, dramatic increase in malignant cells, known as blast crisis. Median age of diagnosis is 66 years; incidence of the disease increases with age. Despite tremendous advances in BCR-ABL tyrosine kinase inhibitor therapies, the majority of patients relapse if therapy is discontinued, in part as a result of dormant cancer stem cell resistance. This work suggests a novel mechanism for overcoming cancer stem cell resistance to therapy that may prevent relapse and progression.
The estimated prevalence of CML in the United States is 70,000 persons with the disease, projected to steadily increase to approximately 181,000 by 2050. CML is initiated by the mutant BCR-ABL gene, but scientists have not yet identified the cause of the mutation.
University of California - San Diego: http://www.ucsd.edu
This press release was posted to serve as a topic for discussion. Please comment below. We try our best to only post press releases that are associated with peer reviewed scientific literature. Critical discussions of the research are appreciated. If you need help finding a link to the original article, please contact us on twitter or via e-mail.
Analysis of millions of audio files has led one US company to claim that their software can predict how a person’s voice will make a listener feel
Bird flu outbreak now spreading through Midwest poultry could head east with fall migration
A little MRI video seems to settle the decades-old debate about that loud pop of the joints: It's all about bubbles. But imagine an air bag inflating, not the bursting of a balloon.
People who took acetaminophen responded less strongly to happy or sad photos in a small study. It's one of several studies suggesting that there's an overlap with pain and other feelings.
Teachers can become frustrated when students don't seem to try hard when it comes to schoolwork. There's a surprising explanation of why some students might not be putting their best effort forward.
Stress from serious events in first 14 years of life may be risk factor and one trigger for disease, finds Swedish study of 10,000 families
Legislators advance bill to tighten immunisation laws in the face of protest from small band of activists who believe parents should be allowed to opt out
To understand the appeal of extremist ideologies we need to look beyond the usual explanations, says a professor of epidemiology
It's not for the faint hearted but it works in mice. When enough hair is plucked out, an immune signal sent to nearby hair follicles triggers extra hair to grow back
A strange mix of living well and taking risks adds one more puzzle to the narcissistic personality