Clinical and therapeutic significance of genetic profiling in adult T-cell leukemia/lymphoma

Abstract

Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive T-cell malignancy with a poor prognosis. Several genetic analyses using next-generation sequencing have uncovered recurrent mutations and copy number alterations involved in diverse functional pathways, including T-cell receptor/NF-κB signaling, immune surveillance, transcription factors, chemokine receptors, and CIC-ATXN1 complex. In addition to these alterations, recurrent structural variations, including PD-L1 (CD274) and REL truncations, characterize ATLL genome. Recent clinicogenetic studies have linked several genetic alterations, such as PRKCB mutations, to a worse clinical outcome. Using genetic and clinical factors, novel prognostic models have been developed, which outperform previous models based on only clinical factors in prognostic prediction. Furthermore, genetic and epigenetic events influencing response to molecularly targeted therapies, such as mogamulizumab and valemetostat, have also been identified. Collectively, these insights underscore the clinical importance of assessing genetic alterations. This review highlights the latest insights into the genetic landscape of ATLL and their clinical implications, which will facilitate the development of future strategies for targeted and personalized therapy.