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Researchers ID Mechanism Underlying Bone Marrow Failure in Fanconi Anemia

Researchers at the University of Helsinki in Finland and the Dana-Farber Cancer Institute in the USA have identified the mechanism behind bone marrow failure developing in children that suffer from Fanconi anemia. The findings may help to develop new therapies for the disorder. Fanconi anemia (FA) is a genetic disease affecting small children and characterized by bone marrow failure, developmental abnormalities, and predisposition to multiple forms of cancer. The molecular mechanisms behind FA are inherited mutations in genes encoding DNA repair proteins, leading to irreversible bone marrow failure. The exact mechanisms of how these genetic mutations lead to the exhaustion of stem cells from the bone marrow have been unknown. Now, the researchers have identified a cause for this failure. The findings were published online on September 29, 2020 in Cell Stem Cell. The article is titled “MYC Promotes Bone Marrow Stem Cell Dysfunction in Fanconi Anemia.” “The results open new paths for developing novel therapies for the disease, for which the only curative treatment currently available is stem cell transplantation. Understanding the mechanism of bone marrow failure better can help to plan stem cell transplantations and to develop new therapies for milder forms of Fanconi anemia,” says Anniina Färkkilä (photo), MD, PhD, Docent and Clinical Researcher at the University of Helsinki, and Specialist in Obstetrics and Gynecology at Helsinki University Hospital. In the study, researchers at the University of Helsinki analyzed the gene expression of individual cells, and found, to their surprise, overexpression of the MYC gene in the bone marrow stem cells of patients with Fanconi anaemia. MYC is one of the best-known genes regulating the formation of malignant tumors. Functional experiments demonstrated that MYC overexpression resulted in the division of stem cells and their detachment from the bone marrow.

“The overexpression of the MYC gene was caused by inflammation mediators, and it led to an abnormal presence of stem cells in the circulation of patients suffering from Fanconi anemia. In mouse experiments, a MYC inhibitor reduced stem cell detachment, but at the same time it also reduced cell proliferation,” Dr. Färkkilä noted.

This suggested that MYC, upregulated in the stem cells due to the inflammatory stress signals, was required for the survival of the stem cells, but as a side effect led to the detachment from the bone marrow niche, and the development of bone marrow failure in FA patients.
Identifying the mechanism associated with bone marrow failure should also help to develop biomarkers for premalignant states in patients with Fanconi anaemia.

“The DNA repair genes defective in FA often result in the development of a number of cancers, which also makes the findings potentially significant in relation to other cancer types, such as ovarian cancer,” Dr. Färkkilä said.

[Press release] [Cell Stem Cell abstract]

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Graphical abstract of article. (Credit: Cell Stem Cell).