Stem Cell Proteostasis Disruption in Ribosomopathy-associated Bone Marrow Failure and Cancer

Pediatric Cancers

Robert Signer (MCC)

Nicholas Gloude (Rady)

In diseases called ribosomopathies, kids are born with genetic errors that disrupt ribosomes, which are the machines our cells use to make protein. This causes problems in multiple organ systems, especially the blood. Patients often develop reduced blood cell counts and are at increased risk for developing leukemia and other cancers that respond poorly to chemotherapy and treatment. Thus, further research is needed to determine the factors that cause these blood disorders so that we can develop new treatments to help these patients and decrease the likelihood that they develop cancer. Recent findings suggest that genetic errors that disrupt ribosomes can cause cells to make faulty proteins that fold into the wrong shape and work incorrectly. This stresses our cells and makes them function poorly. We discovered that blood-forming stem cells, which are cells in our bone marrow that produce blood cells throughout our lives, are very sensitive to accumulation of misfolded proteins. This raises the possibility that protein stress in ribosomopathy patients makes their stem cells malfunction leading to blood disorders and cancer. Using new technology, we will investigate if blood-forming stem cells in children with ribosomopathies have defective proteins, and whether this impairs their stem cells’ ability to make blood. We will also test if these protein changes make stem cells more likely to become cancerous. Our approach will provide critical new information about how these diseases occur, and could provide new strategies for treating these children and preventing their development of cancer.