Chronic lymphocytic leukemia (CLL) represents one of the most common types of leukemia in adults and has a widely variable natural history in terms of time to development of symptoms and overall survival. Several well-designed studies using classic karyotype analysis and then interphase cytogenetics demonstrated that patients with either of two genetic abnormalities, del(11q22.3) or del(17p13.1), have a reduced time to developing symptoms, abbreviated remission following therapy, and ultimately shorter survival. Because del(11q22.3) is more frequently observed, much attention has been focused on determining which gene(s) are lost at the 11q22.3 locus that lead to poor prognosis. While several coding and non-coding genes are found in this minimally deleted region of del(11q22.3), the ataxia telangiectasia mutated (ATM) gene has generated the most interest due to its known importance in double-stranded DNA repair as well as p53 activation with subsequent cell cycle arrest and/or apoptosis. ATM is a very large gene (more than 150 kb and 62 coding exons) that makes detailed study of single nucleotide polymorphisms (SNPs) and mutations challenging. Furthermore, loss of gene function in the absence of a dominant mutation generally requires loss of the alternative allele through mutation or epigenetic silencing; thus, cases with genetic defects may or may not have complete loss of protein function. Despite this, several groups have examined CLL cells for evidence of ATM mutations and found these to be present in up to 30 percent of patients. Until recently, we have been left with the question of whether ATM mutations and del(11q22.3) represent an actual mechanism of pathogenesis and progression in CLL, or are instead only surrogate markers of genomic instability. In a recent issue of the Journal of Clinical Oncology, the authors advance our understanding of the importance of del(11q22.3) in CLL by taking a unique, comprehensive approach to address the importance of loss of one versus two alleles of ATM. Their data demonstrate that ATM mutations are quite common (36 percent) in patients bearing the del(11q22.3) abnormality, and that the loss of one allele by deletion and the other by functional mutation results in complete loss of ATM function. Most importantly, they demonstrate that this loss of function occurs with a detrimental phenotype, with these patients having a significantly reduced survival. As would be expected with silencing of a tumor suppressor gene important in the pathogenesis of a disease, allele-specific deletions occurred at the greatest percentage when mutations were present in the alternative allele, and with disease progression in a subset of patients, mutations and increased percentage deletions developed concurrently. Unlike many other adverse prognostic factors [i.e., del(17p13.1), ZAP-70 over-expression, unmutated IgVH gene status], ATM mutations appear to be independent in this analysis. This paper, therefore, provides both an important biomarker for predicting CLL outcome and firm evidence that ATM is an important gene in the pathogenesis of CLL.
In Brief
Beyond describing "just another biomarker," the authors of this paper are to be commended for performing detailed functional assessment of ATM in which they show that CLL patient cells bearing both ATM mutations and deletions respond to DNA-damaging agents differently at a protein level with respect to functional pathways. For many years, it has been known that irradiation and select DNA-damaging agents activate the ATM pathway and that cells deficient in this pathway are more sensitive to both apoptosis and also eventual transformation presumably through acquisition of additional genomic mutations. The finding of true loss of ATM function in a subset of CLL with an associated phenotype provides a justification to generate novel therapies for this patient population. CLL cells with dysfunctional ATM should be unique from all other cells in the body, potentially making it possible to develop agents that target only these cells. Additionally, this work raises other questions that now should be aggressively pursued with respect to ATM investigation. For example, are there alternative pathways such as epigenetic silencing by promoter methylation or over-expression of miRNAs that silence translation of this important protein? Might there be specific SNPs in ATM that produce variable transcription, translation, or splicing and ultimately lead to protein dysfunction? As we move forward with investigative studies in CLL, Dr. Stankovic’s extensive work clearly supports detailed study of ATM as well as therapies that can target cells with ATM defects.
Competing Interests
Dr. Byrd indicated no relevant conflicts of interest.
