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Researchers Identify Molecular Target and Develop Experimental Treatment for Fanconi Anemia

NEW YORK (GenomeWeb) – Researchers at Cincinnati Children’s Hospital Medical Center have devised an experimental platform to test new therapies for patients with pre- and postnatal Fanconi anemia (FA) conditions, including anemia and cancer.

The team collected induced pluripotent stem cells from skin and connective tissue of FA patients and injected them into humanized mouse models to study their genetic and molecular development. As they reported today in Stem Cell Reports, the researchers found that the stem cells maintained their pluripotency even with the defective FA DNA repair pathway, but they soon underwent profound G2 arrest, with the defective pathway blocking cell division and causing apoptosis.

Mechanistic studies of the dying stem cells found that G2-phase FA-deficient iPSCs possess large γH2AX-RAD51 foci, which form in response to and indicate accrued DNA damage. The team further found that this correlated with activated DNA-damage signaling through CHK1, which serves as a DNA regulator during cell division. Inhibiting CHK1 allowed the stem cells to override the errors in the FA pathway and grow normally.

"CHK1 inhibition specifically rescued the growth of FA-deficient iPSCs for prolonged culture periods, surprisingly without stimulating excessive karyotypic abnormalities," the researchers wrote. "These studies reveal that iPSCs possess hyperactive CHK1 signaling that restricts their self-renewal in the absence of error-free DNA repair."

Senior author Susanne Wells, director of the epithelial carcinogenesis and stem cell program at Cincinnati Children's, and her colleagues believe that these findings point to a possible therapeutic strategy for all manifestations of FA.

"A key question for us is what type of DNA repair kicks in under these conditions — and is it error free or error prone?" Wells said in a statement. "A novel mode of emergency DNA repair might indeed be discovered in the iPSC cells. We believe some type of compensatory DNA repair must be driven by CHK1 inhibition when cells have FA pathway loss, otherwise the cells would have died off very quickly."

The team plans to do follow-up studies in humanized and genetically engineered mouse models, using the CHK1 inhibitor to improve embryonic development and post-birth fitness in mice with deficient FA pathways. They will screen for disease-causing gene mutations as the mice age.

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