白血病を引き起こすウイルスに関連した疾患に対する新たな創薬標的を発見(A new drug target identified for diseases associated with leukemia-causing virus)

2024-07-22 ペンシルベニア州立大学(PennState)

<関連情報>

• https://www.psu.edu/news/research/story/new-drug-target-identified-diseases-associated-leukemia-causing-virus/
• https://www.nature.com/articles/s41467-024-49737-5

チロシンキナーゼKDRはHTLV-1感染T細胞の生存に必須で、Taxオンコプロテインを安定化させる The tyrosine kinase KDR is essential for the survival of HTLV-1-infected T cells by stabilizing the Tax oncoprotein

Suchitra Mohanty,Sujit Suklabaidya,Alfonso Lavorgna,Takaharu Ueno,Jun-ichi Fujisawa,Nyater Ngouth,Steven Jacobson & Edward W. Harhaj
Nature Communications  Published:25 June 2024
DOI:https://doi.org/10.1038/s41467-024-49737-5

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) infection is linked to the development of adult T-cell leukemia/lymphoma (ATLL) and the neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax oncoprotein regulates viral gene expression and persistently activates NF-κB to maintain the viability of HTLV-1-infected T cells. Here, we utilize a kinome-wide shRNA screen to identify the tyrosine kinase KDR as an essential survival factor of HTLV-1-transformed cells. Inhibition of KDR specifically induces apoptosis of Tax expressing HTLV-1-transformed cell lines and CD4 + T cells from HAM/TSP patients. Furthermore, inhibition of KDR triggers the autophagic degradation of Tax resulting in impaired NF-κB activation and diminished viral transmission in co-culture assays. Tax induces the expression of KDR, forms a complex with KDR, and is phosphorylated by KDR. These findings suggest that Tax stability is dependent on KDR activity which could be exploited as a strategy to target Tax in HTLV-1-associated diseases.