Genetic alterations in adult T‐cell leukemia/lymphoma
Open Access
- 29 July 2017
- journal article
- review article
- Published by Wiley in Cancer Science
- Vol. 108 (9), 1719-1725
- https://doi.org/10.1111/cas.13303
Abstract
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell neoplasm with a dismal prognosis, caused by human T-cell leukemia virus type-1 (HTLV-1) retrovirus. A long latency period from HTLV-1 infection to ATL onset suggests that not only HTLV-1 proteins, such as Tax and HBZ, but also additional genetic and/or epigenetic events are required for ATL development. Although many studies have demonstrated the biological functions of viral genes, alterations of cellular genes associated with ATL have not been fully investigated. Recently, a large-scale integrated genetic analysis has revealed the entire landscape of somatic aberrations in ATL. This neoplasm is characterized by frequent gain-of-function alterations in components of the T-cell receptor/NF-κB signaling pathway, including activating mutations in the PLCG1, PRKCB, CARD11, and VAV1 genes, and CTLA4-CD28 and ICOS-CD28 fusions. Importantly, molecules associated with immune surveillance, such as HLA-A/B, CD58, and FAS, are affected recurrently. Among them, one notable lesion occurs as frequent structural variations that truncate the PD-L1 3′-untranslated region, leading to its overexpression. Other genetic targets include transcription factors (IRF4, IKZF2, and GATA3) and chemokine receptors (CCR4, CCR7, and GPR183), which are functionally relevant in normal T cells. A substantial proportion of ATL cases show widespread accumulation of repressive epigenetic changes, such as trimethylation of histone H3 lysine 27 and DNA hypermethylation of CpG islands, which coordinately modulate multiple pathways, including Cys2-His2 zinc finger genes involved in silencing retroelements. Here we review the current understanding of the genetic/epigenetic aberrations in ATL, focusing on their relevance in its molecular pathogenesis.Keywords
Funding Information
- Japan Agency for Medical Research and Development (15Ack0106014h0002, 15im0210102h0001)
This publication has 65 references indexed in Scilit:
- PKCα and PKCβ cooperate functionally in CD3-induced de novo IL-2 mRNA transcriptionImmunology Letters, 2013
- Endogenous viruses: insights into viral evolution and impact on host biologyNature Reviews Genetics, 2012
- Combined Genetic Inactivation of β2-Microglobulin and CD58 Reveals Frequent Escape from Immune Recognition in Diffuse Large B Cell LymphomaCancer Cell, 2011
- Crystal Structure and Allosteric Activation of Protein Kinase C βIICell, 2011
- Antigen Receptor Signaling to NF- B via CARMA1, BCL10, and MALT1Cold Spring Harbor Perspectives in Biology, 2010
- Embryonic stem cells use ZFP809 to silence retroviral DNAsNature, 2009
- GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiationNature Reviews Immunology, 2009
- Targeting the protein kinase C family: are we there yet?Nature Reviews Cancer, 2007
- Isolation and characterization of retrovirus from cell lines of human adult T-cell leukemia and its implication in the disease.Proceedings of the National Academy of Sciences of the United States of America, 1982
- Detection and isolation of type C retrovirus particles from fresh and cultured lymphocytes of a patient with cutaneous T-cell lymphomaProceedings of the National Academy of Sciences of the United States of America, 1980