| RRC ID |
62329
|
| 著者 |
Watanabe T, Yamashita S, Ureshino H, Kamachi K, Kurahashi Y, Fukuda-Kurahashi Y, Yoshida N, Hattori N, Nakamura H, Sato A, Kawaguchi A, Sueoka-Aragane N, Kojima K, Okada S, Ushijima T, Kimura S, Sueoka E.
|
| タイトル |
Targeting aberrant DNA hypermethylation as a driver of ATL leukemogenesis by using the new oral demethylating agent OR-2100.
|
| ジャーナル |
Blood
|
| Abstract |
Adult T-cell leukemia-lymphoma (ATL) is an aggressive hematological malignancy of CD4+ T cells transformed by human T-cell lymphotropic virus-1 (HTLV-1). Most HTLV-1-infected individuals are asymptomatic, and only 3% to 5% of carriers develop ATL. Here, we describe the contribution of aberrant DNA methylation to ATL leukemogenesis. HTLV-1-infected T-cells and their uninfected counterparts were separately isolated based on CADM1 and CD7 expression status, and differentially methylated positions (DMPs) specific to HTLV-infected T cells were identified through genome-wide DNA methylation profiling. Accumulation of DNA methylation at hypermethylated DMPs correlated strongly with ATL development and progression. In addition, we identified 22 genes downregulated because of promoter hypermethylation in HTLV-1-infected T cells, including THEMIS, LAIR1, and RNF130, which negatively regulate T-cell receptor (TCR) signaling. Phosphorylation of ZAP-70, a transducer of TCR signaling, was dysregulated in HTLV-1-infected cell lines but was normalized by reexpression of THEMIS. Therefore, we hypothesized that DNA hypermethylation contributes to growth advantages in HTLV-1-infected cells during ATL leukemogenesis. To test this idea, we investigated the anti-ATL activities of OR-1200 and OR-2100 (OR21), novel decitabine (DAC) prodrugs with enhanced oral bioavailability. Both DAC and OR21 inhibited cell growth, accompanied by global DNA hypomethylation, in xenograft tumors established by implantation of HTLV-1-infected cells. OR21 was less hematotoxic than DAC, whereas tumor growth inhibition was almost identical between the 2 compounds, making it suitable for long-term treatment of ATL patient-derived xenograft mice. Our results demonstrate that regional DNA hypermethylation is functionally important for ATL leukemogenesis and an effective therapeutic target.
|
| 巻・号 |
136(7)
|
| ページ |
871-884
|
| 公開日 |
2020-8-13
|
| DOI |
10.1182/blood.2019003084
|
| PII |
S0006-4971(20)61801-8
|
| PMID |
32391874
|
| MeSH |
Administration, Oral
Adult
Aged
Animals
Antineoplastic Agents / administration & dosage*
Cell Transformation, Viral / drug effects
Cell Transformation, Viral / genetics
Cells, Cultured
DNA Methylation / drug effects*
DNA Methylation / genetics
Demethylation / drug effects
Drugs, Investigational / therapeutic use
Female
Gene Expression Regulation, Leukemic / drug effects
HTLV-I Infections / complications
HTLV-I Infections / drug therapy*
HTLV-I Infections / genetics
Human T-lymphotropic virus 1 / drug effects
Human T-lymphotropic virus 1 / physiology
Humans
Leukemia-Lymphoma, Adult T-Cell / drug therapy*
Leukemia-Lymphoma, Adult T-Cell / genetics
Mice
Mice, Inbred BALB C
Mice, Knockout
Molecular Targeted Therapy / methods
Pyridines / administration & dosage*
Xenograft Model Antitumor Assays
Young Adult
|
| IF |
17.794
|
| リソース情報 |
| ヒト・動物細胞 |
ATN-1(RCB1440)
ILT-Mat(RCB0475)
TL-Mor(RCB1881) |
