State: Missouri

Funded by the Dick Vitale Gala with a gift from Derek and Christin Thompson in memory of Bryan Lindstrom

Bone marrow failure syndromes are a collection of disorders characterized by inadequate production of blood cell lineages from a common progenitor, the hematopoietic stem cell. Dyskeratosis congenita is an inherited bone marrow failure syndrome that comes to clinical attention during early childhood, and is associated with high rates of malignancy in children and young adults, with cancer being a major cause of death in patients. DNA sequencing efforts have established that dyskeratosis congenita has a clear genetic determinant, with patients carrying mutations in their DNA that affect the function of telomerase, a dedicated protein complex that is primarily responsible for maintaining the structure of our chromosomes.

Research regarding dyskeratosis congenita has been hampered by a lack of adequate models. In this proposal we are using genetically engineered human pluripotent stem cells to precisely determine the role that TERC, one of the main components of the telomerase complex, plays in bone marrow failure and cancer in children afflicted with dyskeratosis congenita.  Using our innovative model, we will understand the importance of TERC for stem cell regulation and blood development. Recently we developed the technology to differentiate these stem cells in a controlled, quantitative fashion, to become any particular blood cell type present in the circulatory system. This allows us to reproduce the clinical effect of this disease, in a tissue culture dish, and therefore precisely understand the disease progression in dyskeratosis congenita. Our goal is to help delineate novel treatment strategies against dyskeratosis congenita, a condition that currently has no cure.

Hematopoietic stem cells (HSCs) are responsible for the lifelong regeneration of the blood and bone marrow.  During the lifetime of an individual, genetic mutations can occur in HSCs that slightly alter their properties, potentially leading to diseases of excessive or deficient production of blood cells.  When myeloid cells are chronically affected, these conditions fall into two main categories called myeloproliferative neoplasms (MPN) and myelodysplastic syndromes (MDS).  These disorders are the most common blood cancers in adults with ~20,000 new cases diagnosed each year in the United States.  While these diseases themselves present significant problems such as excessive bleeding and more susceptibility to infections, in a significant number of these patients the disease transforms to a leukemia that is much more difficult to treat and rapidly proves fatal (typically about five months). It is important to identify the genetic processes associated with progression of MDS and MPN to leukemia to improve treatment of these patients.  I believe we have identified a new pathway that facilitates this process by identifying a gene that is genetically mutated specifically in the leukemia phase of the disease, but not the preceding MPN phase.  The goals of this work are to develop new models to understand these processes, and to identify factors to improve the treatment outcomes of such patients.  As there are no effective therapies for these patients that progress to leukemia, any findings that improve the diagnosis and treatment of these patients would represent a significant advance in this field.

2013 Vintner Grant – Funded by The Wine Celebration

In Honor of Fred and Mary Constant, Jeff and Valerie Gargiulo,

Dick and Ann Grace, Fred and Sally Schweiger,

and Lowell and Janet Herrero

Funded by The Hearst Foundation