TY - JOUR
T1 - ORP4L is a prerequisite for the induction of T-cell leukemogenesis associated with human T-cell leukemia virus 1
AU - Zhong, Wenbin
AU - Cao, Xiuye
AU - Pan, Guoping
AU - Niu, Qun
AU - Feng, Xiaoqin
AU - Xu, Mengyang
AU - Li, Mingchuan
AU - Huang, Yu
AU - Yi, Qing
AU - Yan, Daoguang
N1 - Funding Information:
This work was supported by National Science Foundation of China (NSFC) grant 32071280 and 8177043 (D.Y.), Major Research Program of Guangdong Science and Technology grant 2017A030308002 (D.Y.), and NSFC Grant for Young Scientists of China 31900548 (W.Z.).
Publisher Copyright:
© 2022 American Society of Hematology
PY - 2022/2/17
Y1 - 2022/2/17
N2 - 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.
AB - 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.
KW - Animals
KW - Apoptosis
KW - Carcinogenesis/immunology
KW - Cell Proliferation
KW - Gene Expression Regulation, Leukemic
KW - Gene Products, tax
KW - HTLV-I Infections/complications
KW - Human T-lymphotropic virus 1/isolation & purification
KW - Humans
KW - Leukemia-Lymphoma, Adult T-Cell/genetics
KW - Mice
KW - Prognosis
KW - Receptors, Steroid/genetics
KW - T-Lymphocytes/immunology
KW - Tumor Cells, Cultured
KW - Xenograft Model Antitumor Assays
UR - http://www.scopus.com/inward/record.url?scp=85124602193&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85124602193&partnerID=8YFLogxK
U2 - 10.1182/blood.2021013579
DO - 10.1182/blood.2021013579
M3 - Article
C2 - 34797912
AN - SCOPUS:85124602193
SN - 0006-4971
VL - 139
SP - 1052
EP - 1065
JO - Blood
JF - Blood
IS - 7
ER -