Accelerate Genomic Aging in Congenital Neutropenia
Abstract
Transformation to a myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) is perhaps the major clinical concern in patients with severe congenital neutropenia (SCN) and Shwachman-Diamond syndrome (SDS), with a cumulative risk of MDS/AML of more than 20%. The prognosis of patients with SCN or SDS who develop MDS/AML is poor and treatment options are limited. However, the molecular mechanisms contributing to transformation to MDS/AML in these disorders are poorly understand, limiting the development of new therapies or strategies for risk stratification or early detection. In this proposal we test the novel hypothesis that premature genomic aging of hematopoietic stem cells (HSCs) in patients with SCN and SDS contributes to the high rate of transformation to MDS/AML. Each time an HSC divides, it has a chance of acquiring a new mutation. Thus, the number of mutations in an HSC provides an estimate of its genomic age. We have developed a novel assay to measure the mutation burden in HSCs using either blood or bone marrow. Using this assay, we published a paper showing that mutations accumulate in HSCs as a function of age and likely accounts for the increased incidence of AML/MDS in the elderly. It follows, that conditions that increase the rate with which HSCs accumulate mutations will result in an increased incidence of AML/MDS and presentation at an earlier age.
Document Details
- Document Type
- Technical Report
- Publication Date
- Aug 01, 2015
- Accession Number
- AD1001757
Entities
People
- Daniel C. Link
Organizations
- University of Washington