The ATM serine-threonine kinase plays a central role in the cellular response to DNA damage including chromosomal double-strand breaks that arise endogenously or after exposure to DNA-damaging agents such as ionizing radiation and radiomimetic drugs. Inherited mutations in the ATM gene cause ataxia-telangiectasia (A-T), a multisystem disorder associated with immunodeficiency and predisposition to certain lymphoid cancers.
In children, ATM deficiencies frequently result in the development of T lymphoid cancers with germline translocations between the T-cell receptor (TCR) locus and a 450 kb region on human chromosome 14. Approximately 70percent of recurrent translocations in human T-cell acute lymphoblastic leukemias (T-ALL) have been observed to involve TCR genes.
Researchers at the Center for Childhood Cancer Research, including Craig H. Bassing, PhD, have developed an ATM−/− deficient-transgenic mouse model to study the effect of germline TCR gene translocations on the development of T-ALL.
Studies revealed that germline TCR translocations that result in deletion of the Bcl11b tumor suppressor gene cause mice to develop human-like T-ALL disease.
Additional studies are underway to use ATM−/− deficient transgenic mice to better understand the contribution of inherited TCR translocations to the etiology of human T-ALL with ATM deficiencies.
Also, the ATM−/− mouse model represents a unique preclinical opportunity to identify and develop new cancer therapies to treat T-ALL associated with pediatric ATM deficiencies.