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

SIMPLE SUMMARY: In this review paper, we aim to summarize recent findings of genomic alterations found in adult T-cell leukemia/lymphoma (ATLL), which is an incurable disease induced by a virus; human T-cell leukemia virus type 1 (HTLV-1). Genomic alterations of ATLL have been comprehensively analyzed and the identified alterations and HTLV-1 infection synergistically act for ATLL development. As HTLV-1 is an endemic disease, ATLL frequently occurs in the endemic areas. Current clinicogenomic analyses suggest the existence of regional difference in ATLL pathophysiology. From a clinical perspective, several studies identified alterations that act as predictive markers and that a part of the alterations can be targetable in ATLL. The alterations can be leveraged to improve ATLL prognosis. 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.