iPS cells hint that Fanconi anemia is a fetal disease
Fanconi anemia (FA) is a genetic disease that results in a wide range of growth defects, including too often cancer. At the molecular level, FA leads to compromised DNA repair. In healthy individuals, DNA damage activates two FA proteins, FANCD2 and FANCI. These proteins bind the relevant chromatin and enforce homologous recombination and translesion synthesis. Despite its wide effects, the most severe abnormalities are hematopoietic. Although patients can live for decades, symptoms are common in early childhood and very little is known about the early phases of the disease progression. The Megumu Saito lab therefore prepared an iPS cell model to investigate these early stages.
The lab acquired fibroblasts from six FA patients and then reprogrammed the cells to the pluripotent state (iPS cells). To identify molecular mechanisms in the pathology, some clones from the patient-iPS cell clones had a normal FA gene induced that resulted in the expression of healthy FANCD2. Clones that received this correction expressed a much higher number of hematopoietic lineage cells than those that did not and expressed a far more genes involved in hematopoiesis. According to Assistant Professor Akira Niwa, one of the lead authors of the study, this finding shows that FA is a development disease that develops in the womb. "We didn't know the first event of hematopoietic failure. Here we show the first event occurs before birth," he said.
Suzuki NM, Niwa A, Yabe M et al. (2015) Pluirpotent cell models of Fanconi anemia identify the early pathological defect in human hemoangiogenic porgenitors. Stem Cells Translational Medicine
Online publication: March 11, 2015