Bone marrow infiltrated Lnc-INSR induced suppressive immune microenvironment in pediatric acute lymphoblastic leukemia.

Abstract

Immune escape due to immunosuppressive microenvironments, such as those associated with regulatory T (Treg) cells is highly associated with initial occurrence and development of solid tumors or hematologic malignancies. Here, we employed high-throughput transcriptome screening to demonstrate immunosuppression-associated increases in the long noncoding (lnc) RNA lnc-insulin receptor precursor (INSR), which was corrected with INSR expression in CD4+ T cells extracted from the bone marrow of patients with childhood acute T lymphoblastic leukemia. Loss-of-function and gain-of-function assays in vitro and in vivo revealed that membrane-localized and cytoplasm-localized lnc-INSR promoted Treg distribution and decreased the percentage of cytotoxic T lymphocytes, which induced tumor growth. Through direct binding with INSR, lnc-INSR blocked the INSR ubiquitination site, causing abnormal activation of INSR and the phosphatidylinositide 3-kinase/AKT-signaling pathway. These results indicated that lnc-INSR might promote immune suppression by enhancing Treg-cell differentiation and serve as valuable therapeutic targets in the immunosuppressive tumor microenvironment.

• Authors: Yaping Wang, Xiaoyun Yang, Xiaoyan Sun, Liucheng Rong, Meiyun Kang, Peng Wu, Xiaohui Ji, Rufeng Lin, Jie Huang, Yao Xue, Yongjun Fang
• Journal: Cell death & disease (Cell Death Dis) Vol. 9 Issue 10 Pg. 1043 (10 11 2018) ISSN: 2041-4889 [Electronic] England
• PMID: 30310051 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antigens, CD
• RNA, Long Noncoding
• Phosphatidylinositol 3-Kinase
• INSR protein, human
• Receptor, Insulin
• Proto-Oncogene Proteins c-akt

Topics

• Adolescent
• Animals
• Antigens, CD (immunology)
• Bone Marrow (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• Cell Line, Tumor
• Cell Proliferation (physiology)
• Child
• Humans
• Immunosuppression Therapy (methods)
• Jurkat Cells
• Male
• Mice
• Mice, Inbred NOD
• Mice, SCID
• Phosphatidylinositol 3-Kinase (immunology)
• Precursor Cell Lymphoblastic Leukemia-Lymphoma (immunology)
• Proto-Oncogene Proteins c-akt (immunology)
• RNA, Long Noncoding (immunology)
• Receptor, Insulin (immunology)
• Signal Transduction (immunology)
• T-Lymphocytes, Cytotoxic (immunology)
• T-Lymphocytes, Regulatory (immunology)
• Transcriptome (immunology)
• Tumor Microenvironment (genetics)