The Effect of Acquired ATM Mutations on Pediatric Acute T-Cell Lymphoblastic Anemia (T-ALL)
Researchers at the Center for Childhood Cancer Research led by Craig Bassing, PhD, developed a transgenic mouse model to study the effect of acquired somatic ATM mutations on 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.
Children with inherited ATM deficiencies can develop acute T-cell lymphoblastic leukemias (T-ALL) with germline chromosomal translocations. However, acquired somatic ATM mutations have also been identified in several lymphoid cancers including T-ALL.
Frequently, T-ALL subtypes with acquired ATM mutations are extremely aggressive, treatment refractory, and associated with poor clinical outcomes.
Using the CCCR’s mouse model, it was found that somatic inactivation of ATM predisposes mice to T-ALL with chromosomal translocations analogous to those observed in germline ATM-deficient mice. Additional studies revealed that acquired somatic ATM mutations predisposed mice to develop T-ALL that was dependent upon Cyclin D3, a protein that drives immature T-cell proliferation.
Additional studies are underway to use this model system to better understand the contribution of acquired somatic ATM mutations on pediatric T-ALL. The aim is to use the model to identify novel cell cycle targets that can be used to develop therapies to treat unusually aggressive forms of pediatric ALL.