The Role of T-cell Receptor (TCR) Germline Translocations in a ATM−/− Transgenic Mouse Model of Pediatric T-cell Acute Lymphoblastic Leukemia (T-ALL)

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.
 

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