ATM dysfunction across ataxia telangiectasia and leukemias: A systematic review of genetic drivers and functional impact Free

Introduction Ataxia-telangiectasia (AT) is a rare autosomal recessive disorder caused by mutations in the ATM gene. Both germline and somatic alterations in ATM are frequently associated with increased risk of hematologic malignancies. Studying this gene is key to understanding how defects in the DNA damage response contribute to leukemogenesis.

Methods Of 276 articles screened across PubMed, Embase, and Scopus, 25 studies published between 2014 and 2024 met inclusion criteria, focusing on AT/ATM-deficient leukemias. Eligible studies reported on ATM mutation prevalence (germline and somatic), co-mutations, chromothripsis, and miRNA profiles in leukemia. Studies focused solely on lymphoma were excluded. Outcomes assessed included mutation frequencies, risk estimates, survival data, and mechanistic insights into ATM dysfunction and miRNA regulation. A meta-analysis was not performed due to study heterogeneity.

Results ATM alterations were found in 24–25% of patients with chronic lymphocytic leukemia (CLL), with germline variants accounting for up to 24%, significantly higher than in controls (14–16%). High-risk alleles, such as ATM p.L2307F, were observed in 2.3–3% of CLL cases and conferred a tenfold increase in risk.

Individuals with AT showed a markedly elevated risk of leukemia or lymphoma, with a standardized incidence ratio of 56 and cumulative cancer incidence approaching 40% by age 40. Biallelic ATM inactivation occurred in 4–8% of patients and was associated with significantly worse overall survival. Co-mutations were common—SF3B1 (13%), NOTCH1 (22%), and BIRC3 (4%)—and linked to shorter progression-free survival, often under 24 months.

In acute lymphoblastic leukemia (ALL), chromothripsis was observed in 71% of AT-associated cases versus <10% of sporadic ALL, suggesting catastrophic genomic instability with prognostic significance. In CLL, shortened telomeres and impaired telomere maintenance were strongly associated with ATM loss, especially in aggressive subtypes. Functional data showed that 28% of CLL cases with 11q deletion had deficient ATM kinase activity. TP53 and ATM mutations co-occurred in 6.5% of patients, but most cases showed isolated pathway disruption.

In acute myeloid leukemia (AML), overexpression of miR-100 and miR-181a was reported in >60% of pediatric cases. These miRNAs downregulated ATM, promoting cell proliferation. Experimental suppression of these miRNAs restored ATM expression and triggered apoptosis.

Discussion ATM is a critical tumor suppressor and a central determinant of leukemia risk in individuals with AT. In CLL, over 25% of cases harbor ATM alterations—both somatic and germline—often correlating with worse outcomes and shorter treatment-free survival. Prognosis is further compromised by co-mutations and second-hit events such as 11q deletion. Importantly, not all ATM variants result in full loss of function, suggesting that functional assessments like kinase activity may enhance current risk models. ATM deficiency drives widespread chromosomal instability and, in syndromic AT, dramatic chromothripsis. In AML, miRNA-mediated ATM suppression points to a novel, non-coding mechanism contributing to leukemogenesis. Together, these findings support integrating ATM genetic and functional screening into routine evaluation of patients with leukemias to inform risk stratification and therapeutic decisions.