Back to Search
Start Over
ORP4L is a prerequisite for the induction of T-cell leukemogenesis associated with human T-cell leukemia virus 1
- Source :
- Blood. 139:1052-1065
- Publication Year :
- 2022
- Publisher :
- American Society of Hematology, 2022.
-
Abstract
- Human T-cell leukemia virus 1 (HTLV-1) causes adult T-cell leukemia (ATL), but the mechanism underlying its initiation remains elusive. In this study, ORP4L was expressed in ATL cells but not in normal T-cells. ORP4L ablation completely blocked T-cell leukemogenesis induced by the HTLV-1 oncoprotein Tax in mice, whereas engineering ORP4L expression in T-cells resulted in T-cell leukemia in mice, suggesting the oncogenic properties and prerequisite of ORP4L promote the initiation of T-cell leukemogenesis. For molecular insight, we found that loss of miR-31 caused by HTLV-1 induced ORP4L expression in T-cells. ORP4L interacts with PI3Kδ to promote PI(3,4,5)P3 generation, contributing to AKT hyperactivation; NF-κB–dependent, p53 inactivation-induced pro-oncogene expression; and T-cell leukemogenesis. Consistently, ORP4L ablation eliminates human ATL cells in patient-derived xenograft ATL models. These results reveal a plausible mechanism of T-cell deterioration by HTLV-1 that can be therapeutically targeted.
- Subjects :
- Receptors, Steroid
Carcinogenesis
T-Lymphocytes
T cell
Immunology
Apoptosis
Biochemistry
Virus
Mice
hemic and lymphatic diseases
Tumor Cells, Cultured
medicine
Pi
Animals
Humans
Leukemia-Lymphoma, Adult T-Cell
Protein kinase B
Cell Proliferation
Human T-lymphotropic virus 1
Hyperactivation
Gene Expression Regulation, Leukemic
Chemistry
Mechanism (biology)
Gene Products, tax
Cell Biology
Hematology
Prognosis
medicine.disease
HTLV-I Infections
Xenograft Model Antitumor Assays
Human T cell leukemia virus
Leukemia
medicine.anatomical_structure
Cancer research
Subjects
Details
- ISSN :
- 15280020 and 00064971
- Volume :
- 139
- Database :
- OpenAIRE
- Journal :
- Blood
- Accession number :
- edsair.doi.dedup.....d51da57051e6de7c93638950da36898f