Missense mutations in ATM kinase, a master regulator of DNA damage responses, are found in many cancers, but their impact on ATM function and implications for cancer therapy are largely unknown. Here we report that 72% of cancer-associated ATM mutations are missense mutations that are enriched around the kinase domain. Expression of kinase-dead ATM (AtmKD/-) is more oncogenic than loss of ATM (Atm-/-) in mouse models, leading to earlier and more frequent lymphomas with Pten deletions. Kinase-dead ATM protein (Atm-KD), but not loss of ATM (Atm-null), prevents replication-dependent removal of Topo-isomerase I-DNA adducts at the step of strand cleavage, leading to severe genomic instability and hypersensitivity to Topo-isomerase I inhibitors. Correspondingly, Topo-isomerase I inhibitors effectively and preferentially eliminate AtmKD/-, but not Atm-proficientor Atm-/- leukemia in animal models. These findings identify ATM kinase-domain missense mutations as a potent oncogenic event and a biomarker for Topo-isomerase I inhibitor based therapy.DOI:
http://dx.doi.org/10.7554/eLife.14709.001
Ataxia-telangiectasia (A-T) is an autosomal recessive chromosome breakage
disorder caused by mutations in the ATM gene. Typically it
presents in early childhood with progressive cerebellar dysfunction along with
immunodeficiency and oculocutaneous telangiectasia. An increased risk of
malignancy is also associated with the syndrome and, rarely, may be the
presenting feature in small children. We describe a 17-year-old boy with slurred
speech, mild motor delays and learning disability diagnosed with atypical A-T in
the setting of T-cell acute lymphoblastic leukemia. Suspicion for A-T was raised
after review of a peripheral blood karyotype demonstrating rearrangements
involving chromosomes 7 and/or 14. The diagnosis was confirmed after molecular
testing identified a novel homozygous missense variant in ATM
(c.5585T>A; p.Leu1862His) that resulted in protein instability and
abolished serine/threonine protein kinase activity. To our knowledge, this is
the first report of concurrent A-T and lymphoid malignancy diagnoses in an older
child or adult with only mild neurological disease. Our experience suggests that
screening for the disorder should be considered in any individual with lymphoid
malignancy and neurological findings, especially as radiation and certain
chemotherapy protocols are contraindicated in A-T.
Bcl11b is a transcription factor important for T cell development and also a tumor-suppressor gene that is hemizygously inactivated in ~10 % human T cell acute lymphoblastic leukemia (T-ALL) and several murine T-ALL models, including ATM−/− thymic lymphomas. Here we report that heterozygous loss of Bcl11b (Bcl11b+/−) unexpectedly reduced lethal thymic lymphoma in ATM−/− mice by suppressing lymphoma progression, but not initiation. The suppression was associated with a T cell-mediated immune response in ATM−/−Bcl11b+/− mice, revealing a haploid insufficient function of Bcl11b in immune modulation against lymphoma and offering an explanation for the complex relationship between Bcl11b status with T-ALL prognosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-015-0191-8) contains supplementary material, which is available to authorized users.
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