Chimeric transcripts between HTLV-1 and host genome in patients with adult T-cell leukemia-lymphoma

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K16122
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Saga University (2019); Kumamoto University (2018)
• Principal Investigator: Katsuya Hiroo 佐賀大学, 医学部, 助教 (80632041)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: 成人T細胞白血病・リンパ腫 / HTLV-1 / キメラトランスクリプト

Outline of Final Research Achievements

We hypothesized that the integrated provirus generates virus-host chimeric transcripts (CT) may play a role in the clonal selection of the HTLV-1-infected cell. HTLV-1 RNA-capture-seq provided the presence of CTs in 21 out of 30 ATL patients. We next quantified the abundance of CTs by droplet digital PCR, and found that the levels of CTs were similar to those of viral RNAs containing splice junction of HBZ, although the expression levels varied among different ATL cases. Oxford Nanopore sequencing revealed that the HTLV-1 provirus generates various splicing CTs with the host genes in both viral sense and antisense orientations. To clarify the impact of viral integration on clonal expansion, we analyzed HTLV-1-infected Jurkat cells. The integration site analysis showed that some clones were remarkably expanded during the long-term cultivation and some of them harbored CTs with the host genes.

Free Research Field

血液腫瘍学

Academic Significance and Societal Importance of the Research Achievements

HTLV-1感染者のうち約5%のみで予後不良である成人T細胞白血病・リンパ腫(ATL)を発症する。わずか5%の感染者の体内で、どのようにATLクローンが選択されるかは、いまだに不明である。我々は組み込み部位特異的なキメラトランスクリプトが、多くのATLクローンで存在していることを確認した。またHTLV-1感染させたJurkat細胞株を用いたin vitroの研究でもキメラトランスクリプトの存在が確認され、感染クローン毎に増殖速度が異なっていることが確認された。ウイルスとホストのキメラトランスクリプトが新たなATLの発症機序の一つである可能性を示唆した。