Clinical Applications of Genomic Alterations in ATLL: Predictive Markers and Therapeutic Targets

Abstract

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma (PTCL) caused by human T-cell leukemia virus type 1 (HTLV-1). Recent comprehensive genomic analyses have revealed the genomic landscape. One of the important findings of genomic alterations in ATLL is that almost all alterations are subclonal, suggesting that therapeutic strategies targeting a genomic alteration will result in partial effects. Among the identified alterations, genes involved in T-cell receptor signaling and immune escape mechanisms, such as PLCG1, CARD11, and PD-L1 (also known as CD274), are characteristic of ATLL alterations. From a geographic perspective, ATLL patients in Caribbean islands tend to be younger than those in Japan and the landscape differs between the two areas. Additionally, young Japanese ATLL patients frequently have CD28 fusions, compared with unselected Japanese cases. From a clinical perspective, PD-L1 amplification is an independent prognostic factor among every subtype of ATLL case. Recently, genomic analysis using deep sequencing identified a pre-ATLL clone with ATLL-common mutations in HTLV-1 carriers before development, indicating that genomic analysis can stratify cases based on the risks of development and mortality. In addition to genomic alterations, targetable super-enhancers have been identified in ATLL. These data can be leveraged to improve the prognosis of ATLL.