Rinsho Ketsueki. 2017;58(10):2004-2011. doi: 10.11406/rinketsu.58.2004.
Molecular pathogenesis and its therapeutic implication for ATL.
[Article in Japanese]
Ishitsuka K1. Author information Abstract
Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell
malignancy caused by human T-lymphotropic virus type I (HTLV-1).
HTLV-1 related proteins Tax and HTLV-1 bZIP factor induce immortalization and transformation of HTLV-1-infected T-lymphocytes and eventually induce clonal proliferation.
One of the apparent molecular features in ATL cells is abundant genomic abnormalities targeting characteristic pathways, including T-cell receptor signaling and the NF-κB pathway,
G-protein coupled-receptor, including CCR4, and transcriptional regulation.
Moreover, the overexpression of PD-L1 caused by structural variations in the 3'-UTR of the PD-L1 gene has been reported recently, which indicates possible escape of ATL cells from immune-surveillance and its therapeutic application for pharmacological intervention.
The next is the downregulation of microRNAs and tumor suppressors by genome-wide epigenetic abnormalities, especially accumulation of trimethylated H3K27 induced by EZH2.
Among these molecular events frequently observed in ATL cells, treatment targeting CCR4 via a monoclonal antibody (Mab) has been introduced in the clinic, and immune-therapy by therapeutic vaccine with Tax peptide-pulsed dendritic cells, treatment by immune checkpoint inhibitors (ICI) , and treatment targeting EZH1/2 by a small molecule inhibitor are under clinical trial.
Establishment of novel treatment strategies beyond cytotoxic agents for ATL are eagerly anticipated, especially for elderly patients.
HTLV-1 related proteins Tax and HTLV-1 bZIP factor induce immortalization and transformation of HTLV-1-infected T-lymphocytes and eventually induce clonal proliferation.
One of the apparent molecular features in ATL cells is abundant genomic abnormalities targeting characteristic pathways, including T-cell receptor signaling and the NF-κB pathway,
G-protein coupled-receptor, including CCR4, and transcriptional regulation.
Moreover, the overexpression of PD-L1 caused by structural variations in the 3'-UTR of the PD-L1 gene has been reported recently, which indicates possible escape of ATL cells from immune-surveillance and its therapeutic application for pharmacological intervention.
The next is the downregulation of microRNAs and tumor suppressors by genome-wide epigenetic abnormalities, especially accumulation of trimethylated H3K27 induced by EZH2.
Among these molecular events frequently observed in ATL cells, treatment targeting CCR4 via a monoclonal antibody (Mab) has been introduced in the clinic, and immune-therapy by therapeutic vaccine with Tax peptide-pulsed dendritic cells, treatment by immune checkpoint inhibitors (ICI) , and treatment targeting EZH1/2 by a small molecule inhibitor are under clinical trial.
Establishment of novel treatment strategies beyond cytotoxic agents for ATL are eagerly anticipated, especially for elderly patients.
KEYWORDS:
ATL; Molecular pathogenesis; Novel therapy- PMID:
- 28978842
- DOI:
- 10.11406/rinketsu.58.2004
- [Indexed for MEDLINE]
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