The Diamond Blackfan Anemia Foundation is pleased to announce the funding of another exciting research project. A grant for $35,000 was awarded to Daniel Finley, Ph.D. for his project entitled, “A new mode of ribosome regulation specific to reticulocytes.”
Dr. Daniel Finley, a well-established investigator and a professor at Harvard University, is new to the DBA field. He will be collaborating with Mark Fleming, MD, DPhil of Boston Children’s Hospital. Dr. Finley works on a system by which proteins are targeted for destruction within cells. His interest in DBA stems from recent work in his lab where he identified a gene that targets ribosomal proteins for destruction in maturing reticulocytes. This is a highly original project that is very likely to provide important insight into the regulation of ribosome stability in erythroid precursors, which will be of major interest for DBA research. In addition, it could potentially unravel a new therapeutic avenue for treating DBA.
Dr. Finley, Dr. Fleming, and Anthony Nguyen stated,
We wish to thank the DBAF for its support of our work on red blood cell differentiation. Over the years, we have had the opportunity to study a number of genetic mutant strains of mice with anemia. Unexpectedly, one of these anemic mouse strains carried a mutation in a gene that marks proteins to be degraded. We found that these animals have exceptionally high ribosome levels due to a failure of ribosome elimination, which normally occurs in red blood cells as they mature. This is the opposite of DBA, which is most often due to a defect in ribosome production. An unusual mutant like this can allow us to think about the problem of DBA in a new way, and has the potential to provide significant insights into the disease. With funding from the DBAF, we will be able to test whether inhibiting this protein, and thus preserving ribosomes, could alleviate the anemia seen in DBA.
It has always been fascinating that the major cell type affected in DBA is red blood cells, which are the only cells in the body that lack ribosomes. It should be pointed out that erythroid progenitors need ribosomes to make proteins needed for proliferation and differentiation, but at the late reticulocyte stage, ribosomes are eliminated so the mature red blood cell can focus on oxygen delivery. Dr. Finley seems to have come across the pathway by which ribosomes are eliminated from maturing reticulocytes. Mutations in the gene he is studying in mice affect late erythroid maturation and this results in anemia.
This is not the stage of erythroid development affected in DBA patients, so the human form of Finley’s gene is likely not a DBA gene. Despite this, his gene may be relevant to DBA. It turns out that since the product of this gene targets ribosomal proteins for destruction, loss of its function leads to higher levels of ribosomal proteins. Since most cases of DBA are caused by reduced amounts of ribosomal proteins, Dr. Finley is proposing that drugs that inhibit the enzyme encoded by his gene may raise ribosomal protein levels and thereby have therapeutic value in DBA.