Accession Number : AD1048424


Title :   Accelerate Genomic Aging in Congenital Neutropenia


Descriptive Note : Technical Report,15 Jul 2014,14 Jul 2017


Corporate Author : Washington University St. Louis United States


Personal Author(s) : Link,Daniel C


Full Text : https://apps.dtic.mil/dtic/tr/fulltext/u2/1048424.pdf


Report Date : 01 Oct 2017


Pagination or Media Count : 35


Abstract : The goal of this research is to define the molecular mechanisms responsible for the markedly increased risk of transformation to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML) in patients with congenital neutropenia. We hypothesize that replicative stress and/or changes in the bone marrow microenvironment in patients with congenital neutropenia leads to a higher rate of accumulation of mutations in hematopoietic stem/progenitor cells (HSPCs), which, in turn, contributes to transformation to MDS/AML. We further hypothesize that G-CSF treatment accelerates the accumulation of mutations in HSPCs. Finally, we hypothesize that truncation mutations of CSF3R, which are common in patients with severe congenital neutropenia (SCN) and are associated with increased G-CSF signaling and transformation to MDS/AML, accentuate the rate of mutation accumulation. We will test these hypotheses in the following Specific Aims. Aim 1. To determine whether HSPCs undergo premature genomic aging in SCN or SDS. We will measure the mutation burden in individual HSPCs from patients with SCN, Shwachman-Diamond syndrome (SDS), cyclic neutropenia, or age-matched healthy controls. Aim 2. To determine whether increased G-CSF signaling accelerates the mutation rate in HSPCs. Here, we will assess the impact of prolonged (6 month) G-CSF therapy on HPSC mutation burden in mice. These data will provide novel insight into the mechanisms of leukemic transformation in CN. They also should provide new insight into the safety of long-term G-CSF therapy in CN. Finally, our novel assay to measure mutation burden in HSPCs may provide an approach to assess DNA damage after exposure to genotoxic agents, such as radiation.


Descriptors :   leukemia , stem cells , mutations , genomics , bone marrow


Subject Categories : Medicine and Medical Research
      Anatomy and Physiology
      Genetic Engineering and Molecular Biology


Distribution Statement : APPROVED FOR PUBLIC RELEASE