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Understanding the Mechanisms Driving Genomic Instability in Adult T-Cell Leukemia/Lymphoma

Adult T-cell Leukemia/Lymphoma (ATLL) is a T-cell malignancy that results from infection by the retrovirus, human T cell lymphotropic virus-1 (HTLV-1). ATLL is endemic to Japan, the Caribbean regions and Latin America. Despite the rare occurrence of the disease, ATLL is a very aggressive malignancy with limited treatment options. Recent studies show that the ATLL patients diagnosed in North America (NA-ATLL), who are largely from the Caribbean region, have extremely poor prognosis as compared to the Japanese ATLL (J-ATLL) patients. A better understanding of the molecular pathogenesis of NA-ATLL is critical to identifying effective treatment measures for these patients. It has been previously shown that genomic instability including extensive chromosomal variations can be frequently found in ATLLs. However, the underlying mechanisms leading to this instability are unclear. Analysis of the mechanism of HTLV-1 action has revealed that the virus, in addition to hijacking the host cell machinery, disrupts DNA repair mechanisms and cell division processes. While the disruption of repair mechanisms could be held accountable for the accumulation of damage in ATLL cells, the precise nature of this disruption has not been fully understood. In proliferating cells, damage to the DNA occurs or is primarily recognized during DNA replication. This indicates that defective DNA replication could be an important factor driving genomic instability in ATLL cells. Possible involvement of replicative defects in the etiology of ATLL is further strengthened by the fact that genomic instability in ATLL cells has been shown to occur at difficult to replicate genomic regions referred to as common fragile sites. Here, using a powerful locus specific approach called the single molecule analysis of replicated DNA (SMARD), we show that perturbed DNA replication is an inherent component of disease manifestation in ATLL patients. Furthermore, our preliminary findings suggest that these changes in DNA replication can be largely attributed to the EP300 inactivating mutations often found among NA-ATLL patients. This study will help elucidate the molecular mechanisms contributing to the marked chemo-resistant feature of NA-ATLL patients, as compared to J-ATLL patients. In addition to increasing our understanding of the mechanisms contributing to ATLL in general, the results from this study may inform new and mechanism-based treatment paradigms that target the replicative defects of this unique disease.
 
 
 No relevant conflicts of interest to declare.
