ATM Mutations in Cancer: Therapeutic Implications

Choi, Minyoung; Kipps, Thomas; Kurzrock, Razelle

doi:10.1158/1535-7163.mct-15-0945

Cited by 361 publications

(310 citation statements)

References 107 publications

(86 reference statements)

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“…Thus, although C-NHEJ is important for genome stability, this pathway may nevertheless facilitate cancer-associated rearrangements, particularly in cells with a defective ATM-mediated DDR. Consistent with this notion, inherited and somatic mutations in ATM have been associated with several types of cancer (29).…”

Section: Discussionmentioning

confidence: 62%

Contribution of canonical nonhomologous end joining to chromosomal rearrangements is enhanced by ATM kinase deficiency

Bhargava

Carson

Lee

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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A likely mechanism of chromosomal rearrangement formation involves joining the ends from two different chromosomal doublestrand breaks (DSBs). These events could potentially be mediated by either of two end-joining (EJ) repair pathways [canonical nonhomologous end joining (C-NHEJ) or alternative end joining (ALT-EJ)], which cause distinct rearrangement junction patterns. The relative role of these EJ pathways during rearrangement formation has remained controversial. Along these lines, we have tested whether the DNA damage response mediated by the Ataxia Telangiectasia Mutated (ATM) kinase may affect the relative influence of C-NHEJ vs. ALT-EJ on rearrangement formation. We developed a reporter in mouse cells for a 0.4-Mbp deletion rearrangement that is formed by EJ between two DSBs induced by the Cas9 endonuclease. We found that disruption of the ATM kinase causes an increase in the frequency of the rearrangement as well as a shift toward rearrangement junctions that show hallmarks of C-NHEJ. Furthermore, ATM suppresses rearrangement formation in an experimental condition, in which C-NHEJ is the predominant EJ repair event (i.e., expression of the 3′ exonuclease Trex2). Finally, several C-NHEJ factors are required for the increase in rearrangement frequency caused by inhibition of the ATM kinase. We also examined ATM effectors and found that H2AX shows a similar influence as ATM, whereas the influence of ATM on this rearrangement seems independent of 53BP1. We suggest that the contribution of the C-NHEJ pathway to the formation of a 0.4-Mbp deletion rearrangement is enhanced in ATM-deficient cells.hromosomal deletion rearrangements have been identified in several cancer genome studies. For example, an analysis of cancer cell lines found somatic deletions with an average size of 0.5 Mbp, some of which caused loss of tumor suppressor genes, including PTEN and RB (1). A likely mechanism for such rearrangements involves aberrant end-joining (EJ) repair that ligates distal ends of two different double-strand breaks (DSBs) on the same chromosome (i.e., distal EJ). Significant insight into deletion rearrangements has been derived from examining V(D)J recombination, which involves EJ repair of programmed DSBs that requires the KU70/KU80 heterodimer that binds DSB ends, DNA ligase 4 (LIG4), and the LIG4 cofactor XRCC4; they are collectively referred to as canonical (classical) nonhomologous end joining (C-NHEJ) (2). Another C-NHEJ factor is XLF, which forms nucleoprotein filaments with XRCC4 to promote LIG4 activity as well as DSB end bridging via an apparent sliding sleeve mechanism (3, 4).Although C-NHEJ is critical for V(D)J recombination of programmed DSBs, the relative importance of this pathway for other EJ-mediated rearrangements is controversial (5). Namely, another EJ repair pathway, alternative end joining (ALT-EJ), can also contribute to rearrangement formation. ALT-EJ is independent of C-NHEJ factors and mediated by LIG1 and/or LIG3 among other factors (5-7). Repair junctions mediated by these EJ pathways sh...

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Section: Discussionmentioning

confidence: 62%

Contribution of canonical nonhomologous end joining to chromosomal rearrangements is enhanced by ATM kinase deficiency

Bhargava

Carson

Lee

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…AML-iPSCs from both cases possessed mutations known to be oncogenic drivers in multiple cancer types, including CNS tumors, such as MLL, ARID1A, ATM, and RAS (Choi et al, 2016; Knobbe et al, 2004; Parsons et al, 2011; Prior et al, 2012; Sausen et al, 2013). To investigate whether AML-iPSCs give rise to normal, non-tumorigenic cell types in the presence of these oncogenes, we differentiated them into the neural and cardiomyocyte lineages (Figure S2).…”

Section: Resultsmentioning

confidence: 99%

Human AML-iPSCs Reacquire Leukemic Properties after Differentiation and Model Clonal Variation of Disease

et al. 2017

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SUMMARY Understanding the relative contributions of genetic and epigenetic abnormalities to acute myeloid leukemia (AML) should assist integrated design of targeted therapies. In this study, we generated induced pluripotent stem cells (iPSCs) from AML patient samples harboring MLL rearrangements and found that they retained leukemic mutations but reset leukemic DNA methylation/gene expression patterns. AML-iPSCs lacked leukemic potential, but when differentiated into hematopoietic cells, they reacquired the ability to give rise to leukemia in vivo and reestablished leukemic DNA methylation/gene expression patterns, including an aberrant MLL signature. Epigenetic reprogramming was therefore not sufficient to eliminate leukemic behavior. This approach also allowed us to study the properties of distinct AML subclones, including differential drug susceptibilities of KRAS mutant and wild-type cells, and predict relapse based on increased cytarabine resistance of a KRAS wild-type subclone. Overall, our findings illustrate the value of AML-iPSCs for investigating the mechanistic basis and clonal properties of human AML.

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“…Targets for ATM catalytic activity include proteins involved in cell-cycle checkpoint arrest (i.e., Chk1 and Chk2), DNA repair (i.e., BRCA1 and RAD51), apoptosis (i.e., p53), and chromatin relaxation (i.e., KAP1). 10 Both heterozygous and homozygous hereditary mutations in ATM result in an increased risk for cancer due to impaired DNA damage repair and genomic instability. Leukemia and lymphoma are the most common cancers reported in individuals with A-T, however breast, thyroid, pancreatic, and other neoplasms have also been observed.…”

Section: Discussionmentioning

confidence: 99%

New diagnosis of atypical ataxia-telangiectasia in a 17-year-old boy with T-cell acute lymphoblastic leukemia and a novel ATM mutation

et al. 2017

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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.

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ATM Mutations in Cancer: Therapeutic Implications

Cited by 361 publications

References 107 publications

Contribution of canonical nonhomologous end joining to chromosomal rearrangements is enhanced by ATM kinase deficiency

Contribution of canonical nonhomologous end joining to chromosomal rearrangements is enhanced by ATM kinase deficiency

Human AML-iPSCs Reacquire Leukemic Properties after Differentiation and Model Clonal Variation of Disease

New diagnosis of atypical ataxia-telangiectasia in a 17-year-old boy with T-cell acute lymphoblastic leukemia and a novel ATM mutation

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