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.
Doctors have used perfect replicas of childrens' hearts to uncover and repair hidden defects
An experiment testing people’s altruism in the face of electric shocks is clear on one thing: we are drawn to these little blasts
Researchers gear up tests in West Africa to see whether blood from Ebola survivors can help people who are sick with the disease. This is part of a broader effort to test therapies in West Africa.
The virus's foray into Europe coincides with peak production of Christmas turkeys, the poultry species most vulnerable to bird flu
A novel kind of nanoparticle could lead to more effective cancer treatments.Patients and doctors often don’t know if surgery to remove cancerous tissue was successful until scans are performed months later. A new kind of nanoparticle could show patients if they’re in the clear much earlier.
One challenge in evaluating the effectiveness of different medical procedures, is that patients behave differently after different procedures. Is this true for patients getting heart surgery?
It is only in the aftermath of treatment that survivors discern that their adrenalin alone wont fuel the rest of their recovery. For many, surviving cancer is followed by even more hardship
Just down the road from Facebook and Google, Dr. Phil Wagner runs a laboratory dedicated to optimizing the performance of some of the world's top athletes. At Sparta Performance Science in Menlo Park, California, Wagner and his team bring the spirit of Silicon Valley to bear on the athletic world, helping athletes find the tiny advantages that add to championships. Join us for a trip inside the lab to see where sports meets science.
Pieter Cohen, an internist in Massachusetts, got interested in dietary supplements several years ago, when some of his …
The risk of overdiagnosis and false positives means the UK may be barking up the wrong tree in trialling a wider target age range for breast screening