Ataxia telangiectasia (A-T) is a rare, genetic immunodeficiency disease that affects multiple organ systems and is characterized by neurodegeneration and cancer predisposition. A-T is caused by recessive mutations in the ataxia telangiectasia mutated (ATM) gene.

While existing animal models have established how ATM mutations contribute to genomic instability and cancer susceptibility, Dr. Wassarman's paper reveals how ATM mutations cause neurodegeneration.

The scientists generated a Drosophila model of A-T, in which neurodeneneration occurs in the absence of induced DNA damage “ as it does in human A-T patients. Thus, Dr. Wassarman's model most faithfully recapitulates neurodegeneration associated with the human disease.

Using this model, Dr. Wassarman and colleagues determined ATM functions normally to prevent neurons from re-entering the cell cycle.

At the end of the day, ATM-dependent arrest of cell growth is critical for both neuron function and tumor suppression, explains Dr. Wassarman. Furthermore, he is excited by the findings, as they point to possible therapeutic potential of CDC25 and other cell cycle inhibitors to treat A-T as well as other neurodegenerative disorders.

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Among the ALL patients, the researchers found an average of 8.79 copy number alterations, a form of genetic change linked to the development and progression of cancer. The most common change was deletion of the gene for Ikaros.

The gene was deleted in 36 (83.7 percent) of the BCR-ABL1 ALL patients, including 76.2 percent of the pediatric and 90.9 percent of the adult cases.

"The loss of the Ikaros gene is a nearly obligatory lesion for the development of BCR-ABL1 ALL," Downing said, "and clearly must be a genetic lesion that is cooperating with BCR-ABL1."

Moreover, a gene known as CDKN2A was deleted in 53.5 percent of the BCR-ABL1 ALL patients, 87.5 percent of whom also had lost the gene for Ikaros. The PAX5 deletion occurred in 51 percent of the BCR-ABL1 ALL patients; and 95 percent of these people were missing the Ikaros gene.

Among the CML patients whose disease converted to ALL, two out of three had the deletion of the Ikaros gene; a lower percentage of those who converted to acute myeloblastic leukemia had the same gene deleted. That finding suggested that the deletion of Ikaros is cooperating with BCR-ABL1 to cause ALL.

"That is an important finding that may give insight into how that transformation occurs, or it may give insight into a better way to treat the disease, if one can figure out how the Ikaros deletion is working," Downing said.

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