Rescuing Mutation May Operate in Bone Marrow Failure

Bone marrow failure syndromes are rare disorders in which the bone marrow does not produce enough blood cells, increasing the risk for life-threatening bleeding, anemia, and infections. While children with these conditions usually will need bone marrow transplantation, a small percentage experience spontaneous remission.

Modern genomic approaches are allowing researchers at The Children’s Hospital of Philadelphia to discover how such remission cases occur, which potentially could lead to a novel approach that will transform the way these devastating conditions are understood and managed.

Their hypothesis is that natural mutations in stem cells or progenitor cells could “rescue” them and overcome the effects of inherited or acquired gene mutations linked to bone marrow failure. They suggest that the process behind the correcting mutations is associated with clonal hematopoiesis. While clonal hematopoiesis typically is considered to be a black cloud because it is implicated in the series of genetic changes that lead to cancerous tumor development, this study suggests that clonal hematopoiesis could brighten the chances of recovery for patients with bone marrow failure syndromes.

“If the majority of blood cells are derived from a single stem cell, which is the mother cell of all blood cells, this is called clonal hematopoiesis,” explained Philip Mason, PhD, a senior scientist for CHOP’s Comprehensive Bone Marrow Failure Center (CBMFC). “Normal blood cell production is from many stem cells. We think that it is likely that a mutation takes place in a stem cell, or progenitor cell, which improves its ability to produce blood cells or even corrects the initial defect.”

Stem cells, or hematopoietic cells, develop in the spongy bone marrow and give rise to all blood cells. Progenitor cells are early descendants of stem cells that can differentiate to form one or more kinds of blood cells, such as red blood cells, platelets, or white blood cells. In bone marrow failure syndromes, the stem cells or progenitor cells are damaged and restrict blood production. Rescuing mutations, in contrast, allow the stem cell to grow and divide, thus giving the mutated blood cells a growth advantage — sometimes to the extent that these mutated blood cells, all derived from a single stem cell, replace the entire blood cell production.

Dr. Mason is principal investigator of a new study that focuses on an inherited bone marrow failure syndrome called Diamond Blackfan Anemia, which affects 5 to 7 infants per million births worldwide. The study team’s plan is to determine the DNA sequence in the blood cells from bone marrow of 20 study participants with Diamond Blackfan Anemia, and then compare it to the sequence of skin cells from the same participants. Along with experts from CHOP’s Center for Biomedical Informatics, the researchers will pinpoint the sequences that only appear in the bone marrow cells, which will help them to identify clones of cells that are likely to carry the characteristics of the rescuing mutations.

Once this bioinformatics analysis is complete, the researchers will perform extensive validation using targeted deep sequencing methodology. This will help them to select candidate genes to be included in future functional studies to test if and how these mutations are capable of correcting the initial defect in ribosome synthesis seen in Diamond Blackfan Anemia that is responsible for the poor production of red cells.

If the study team finds clonal hematopoiesis due to mutations that increase blood cell survival or proliferation, they propose that similar mechanisms likely operate in all inherited bone marrow failure syndromes and possibly in the scenario of acquired aplastic anemia, although the mutations, genes, and pathways affected may differ. Dr. Mason also is a co-investigator of a larger study involving a multidisciplinary team of clinicians and researchers that focuses on 100 patients with acquired aplastic anemia. The lead principal investigator is Monica Bessler, MD, PhD, director of the CBMFC, a collaborative effort between CHOP and the Hospital of the University of Pennsylvania.

“While the study process is similar, it is more complicated because we don’t exactly know the causes of acquired aplastic anemia,” Dr. Mason said. “DNA sequencing and identifying the correcting mutations will help us to find out the disease’s origins, which may be different from patient to patient.”

Dr. Mason, who has investigated bone marrow failure diseases for 17 years, is enthusiastic about his involvement with both studies, which were awarded funding in August by the National Institute of Diabetes and Digestive and Kidney Diseases.

“This kind of study has only become possible in the last few years because of the technical advances in sequencing,” Dr. Mason said. “I’m excited by the possibility that it could work out and lead to better treatments for these patients.”