Clinical application of genomic aberrations in adult T-cell leukemia/lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATL) is an aggressive peripheral T-cell malignancy with a markedly poor prognosis. The low prevalence of ATL among human T-cell leukemia virus type-1 (HTLV-1) carriers and the long latency period before ATL onset suggest that additional genetic lesions are required for ATL leukemogenesis. Recently, a large-scale genetic analysis clarified the entire picture of genetic alterations, identified a number of novel driver genes, and delineated their characteristics. Frequent alterations are observed in the molecules belonging to T-cell receptor/NF-κB signaling and other T-cell-related pathways. A notable feature of the ATL genome is the predominance of gain-of-function alterations, including activating mutations in PLCG1 , PRKCB , and CARD11 . As many as one-fourth of all ATL cases harbor structural variations disrupting the 3′-untranslated region of the PD-L1 gene, leading to immune evasion of tumor cells. The frequency and pattern of these somatic alterations differ among clinical subtypes. Aggressive subtypes are associated with an increased burden of genetic alterations, and higher frequencies of TP53 and IRF4 mutations, PD-L1 amplifications, and CDKN2A deletions than indolent subtypes. In contrast, STAT3 mutations are more characteristic of indolent ATL. Furthermore, these subtypes are further classified into molecularly distinct subsets with a different prognosis by genetic alterations. We present an overview of the current understanding of somatic alterations in ATL, with specific focus on their utility in clinical settings. Furthermore, we highlight their genetic features by exploring their similarities and differences among peripheral T-cell lymphomas.

Efficacy of Corticosteroid Therapy for HTLV-1-Associated Myelopathy: A Randomized Controlled Trial (HAMLET-P)

“…Individuals infected with HTLV-1, including those with HAM, are at risk of developing ATL [33]. Those who have clonal expansion of HTLV-1-infected lymphocytes with ATL-related somatic mutations are at significantly high risk [34][35][36][37]. In this study, one slow progressor taking prednisolone developed ATL, and we retrospectively confirmed that this patient had such clones upon trial enrollment.…”

Aggressive T‐cell lymphomas: 2021 Updates on diagnosis, risk stratification and management

“…More than a third of cases of ATLL show widespread hypermethylation of CpG islands. Methylation pathway genes ( TET2 , DNMT3 , EP300 and IDH2 ) are altered, but less frequently than in AITL 57 . Hypermethylation is one of the silencing mechanisms the MHC1 complex.…”

“…Methylation pathway genes (TET2, DNMT3, EP300 and IDH2) are altered, but less frequently than in AITL. 57 Hypermethylation is one of the silencing mechanisms the MHC1 complex. Polycomb-dependent repression is enhanced in ATLL by trimethylation of histone lysine 27 and affects half the genes in ATLL.…”

Pathogenesis of HTLV-1 infection and progression biomarkers: An overview

“…There is also evidence of an association between genetic biomarkers and ATLL; that is, the genetic profile of the host can contribute to prognosis and can be an important additional tool in the management of affected individuals if properly implemented in endemic areas 97 , 98 , 99 , 100 , 101 . This finding demonstrates the importance of implementing these approaches in our environment.…”