Scientists identify molecule that appears to fuel deadly genetic illness, Fanconi anemia

Fanconi anemia is a complex genetic disorder that is responsible for birth anomalies, organ damage, anemia and cancer. Researchers working on this condition have identified a molecular target and experimental treatment strategy for DNA repair defects responsible for it. The findings of the study were published recently in Stem Cell Reports.

The findings of the study have created a bit of molecular intrigue. The cells with Fanconi anemia (FA) DNA repair defect used in the study were given targeted treatment and post treatment they were able to recover and grow normally.

Susanne Wells, PhD, director of the Epithelial Carcinogenesis and Stem Cell Program in the Cincinnati Children’s Hospital Medical Center (Cancer and Blood Diseases Institute) and lead investigator of the study said that this study provides an experimental platform to test new therapies that could prevent pre- and post-natal Fanconi anemia conditions, which have no cure and limited treatment options. Our findings are just the tip of the iceberg as there are plenty of questions that still need to be answered.

For the study induced pluripotent stem cells (iPSCs) were used the researchers as they can become any cell type in the body. These induced stem cells were created by reprogramming mature skin and connective tissue cells donated by Fanconi anemia patients. They cells had the defective (FA) DNA repair pathway, which typically helps protect the genome from mutations.

The stem cells were closely studied by scientists in laboratory cultures and cells injected into humanized mouse models monitoring their genetic, molecular and developmental progression. Even though the cells had defective FA DNA repair, the stem cells were capable of transforming into different tissues. In fact, humanized mice injected with the defective cells started to form teratomas”benign tumors that contain a haphazard mishmash of cells and tissues of different organ systems. However, it was observed by the researchers that due to the DNA repair defect the pluripotent stem cells were started to get killed by blocking cell division and causing programmed cell death.

It was observed that an enzyme that serves as a DNA regulatory checkpoint during cell division (CHK1) was hyperactive in the stem cells, which seemed to hasten their death. To block the hyperactive enzyme at a critical stage of the stem cell cycle, existing pharmacologic inhibitors of CHK1 were used by the researchers. This enabled them to override what usually are unfixable errors in the FA repair pathway. It was seen that after the targeted treatment, FA-pathway-deficient pluripotent stem cells resumed dividing and expanding normally. It was a surprise to the researchers that the cells resumed growth with chromosome abnormalities.

The researchers speculate that a compensating DNA repair process is engaged in the reinvigorated cells. Wells and colleagues are hopeful that study may point to an approach that treats all clinical manifestations of the disease like anemia and cancer.

Well remarked that an important question that need to be answered is what type of DNA repair kicks in under these conditions and if it is totally error free or prone to errors. He added that it is likely that a novel mode of emergency DNA repair might be discovered in the iPSC cells.  Since, human cells have other DNA repair processes besides the FA repair pathway researchers hope to closely monitor their upcoming experiments for one of these existing DNA repair pathways.

Timothy Chlon, PhD (a research associate in the Wells laboratory) and first author of the study stressed the current results are early and need extensive additional study before becoming clinically relevant. To further their study, the research team plan to follow up this study with additional testing in ‘humanized’ and genetic mouse models.

References:

https://medicalxpress.com/news/2016-01-scientists-molecule-fuel-deadly-genetic.html#nRlv

https://www.sciencenewsline.com/news/2016011217500005.html