Hematopoietic stem cell function in familial platelet disorder therapy
Genetic studies have identified a number of genes that when mutated predispose individuals to blood cancers. In addition, these mutations can promote other health complications throughout their lifetime. For example, children that inherit a mutation in the gene RUNX1 have Familial Platelet Disorder, they live with bleeding problems and, in many cases, autoimmune complications. In addition, affected children have a high incidence of blood cancer during their childhood or later in life. Currently, there are not effective therapies to prevent the development of blood cancer. Patients that develop blood cancers with a RUNX1 mutation are treated with chemotherapy and allogeneic stem cell transplantation.
Project Goals:
Important advances in genome editing technologies provide an opportunity to correct mutations in blood stem cells with high efficiency. The goal of this project is to determine if the correction of the RUNX1 mutation in blood stem cells can restore their normal function and prevent cancer, using a mouse model for Familial Platelet Disorder. These studies may guide future efforts to develop autologous stem cell transplantation protocols that efficiently correct the RUNX1 mutation in the blood stem cells for transplant back into the patient as a curative therapy. The outcome of this study may also serve for the application of similar approaches to other inherited blood cancers.
Project Update 2024:
Children with Familial Platelet Disorder, a disease caused by an inherited mutation in the gene RUNX1, live with bleeding complications and are at risk to developing leukemia in life. Recent advances in gene editing technology have made possible to correct mutations in hematopoietic cells, with promising use in the clinic. These advances suggest that the RUNX1 sequence could be corrected in hematopoietic stem cells from FPD patients before leukemia onset, and placed back to overcome the bleeding complications and prevent leukemia. Our study supports the idea that gene editing strategies aiming to correct the germline RUNX1 mutation in HSCs from FPD patients should only be considered if the technology can achieve high correction efficiency and negligible rates of indels (a type of genetic mutation). Like with other genes with tumor suppressor function, the acquisition of indels may promote transformation.
