Inappropriate costimulation and aberrant DNA methylation as therapeutic targets in angioimmunoblastic T-cell lymphomaReportar como inadecuado




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Biomarker Research

, 5:6

First Online: 08 February 2017Received: 21 October 2016Accepted: 03 February 2017

Abstract

Angioimmunoblastic T-cell lymphoma AITL is one of the most common subtypes of peripheral T-cell lymphoma. Advances in understanding the mutational landscape of AITL have not resulted in improved prognosis nor consensus regarding optimal first-line and second-line treatment.

The recently proposed multistep tumorigenesis model for AITL provides a theoretical framework of AITL oncogenesis. In this model, early mutations in epigenetic modifiers interact with late cooperative mutations to enable malignant transformation. Frequent mutations in epigenetic modifiers suggest that aberrant DNA methylation contributes to AITL oncogenesis. Several research groups have reported findings suggesting that inappropriate costimulation acts as a late cooperative mutation. Drugs targeting inappropriate costimulation have already been approved for the treatment of several malignancies or autoimmune diseases. Additionally, aberrant DNA methylation was recently shown to potentiate inappropriate costimulation in a subset of AITL cases. Therefore, drugs targeting inappropriate costimulation and hypomethylating agents might have synergistic effects. Both offer promising new therapeutic options in AITL treatment.

This commentary summarizes the main findings on aberrant DNA methylation and inappropriate costimulation in AITL and proposes several already approved drugs for AITL treatment. Hopefully, these will contribute to improving the still dismal prognosis of AITL patients.

KeywordsAngioimmunoblastic T-cell lymphoma Multistep tumorigenesis Costimulation DNA methylation Molecular pharmacology Abbreviations2HGR-2-hydroxyglutarate

2OG2-Oxoglutarate

AITLAngioimmunoblastic T-cell lymphoma

Bcl6B cell lymphoma 6

CTLA-4Cytotoxic T-lymphocyte antigen-4

DGKαDiacylglycerol kinase alpha

DNMT3ADNA methyltransferase 3A

HSCsHematopoietic stem cells

IDH2Isocitrate dehydrogenase 2

MAPKMitogen-activated protein kinase

PI3K-Akt-mTORPhosphatidylinositol 3 kinase-Akt-mammalian target of rapamycin

PTCLPeripheral T-cell lymphoma

PTPN7Protein tyrosine phosphatase non-receptor type 7

R-RRelapsed-refractory

Ras-Raf-MAPK-ERKRas-Raf-MAPK-extracellular signal-regulated kinase

RHOARas homologue family member A

TET2Ten-eleven translocation 2

TFHT follicular helper cell

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Autor: Mathijs Willemsen - Harry C. Schouten

Fuente: https://link.springer.com/article/10.1186/s40364-017-0085-8







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