| Leukemia is a malignant proliferative disease that hematopoietic stem cells block at a certain stage in the process of differentiation.It is one of the major diseases endangering children’s life and health.Acute lymphoblastic leukemia(ALL)is the most common subtype in children,accounting for about 75% of leukemia,and the proportion in children younger than 15 years old is approximately 30%.With the development of diagnosis and treatment for ALL,the 5-year disease-free survival rate is over 80-90%in most centers.However,a considerable number of patients eventually die of chemotherapy complications or relapse.In-depth studies on the pathogenesis of chilihood ALL are helpfμl to search for new biological markers and new therapeutic targets,and also provide new diagnostic basis for childhood ALL.The immune system plays a very complex role in the development of tumors.Immune cells play a role in promoting inflammation and carcinogenesis by directly participating in the inflammatory processes.On the other hand,the immune system can clear the diseased cells by performing an immune surveillance function.Studies have shown that the formation of inhibitory immune microenvironment leads to immune escape of tumor cells,which promotes the occurrence of tumor.Regμlatory T cells(Treg)mediated inhibitory immune microenvironment has been shown to play an important role in the initial occurrence and development of solid tumors and hematological malignancies.With the development of high-throughput sequencing technology,researchers have revealed that non-coding RNAs account for more than 95% of the human genome,and the complex interactions between protein-coding RNAs and functional non-coding RNAs play an important role in cancer onset and progression.As one of the important components of non-coding RNAs,long non-coding RNA(lnc RNA)has attracted more and more attention in the tumor fields.Current studies have found that lnc RNA is involved in epigenetic,transcriptional and post-transcriptional regμlation in a variety of ways and it may be a marker for early diagnosis of some diseases.In this study,we obtained bone marrow samples from 3 cases of new-diagnosed childhood ALL and 3controls of healthy children.Monocytes in bone marrow samples were isolated by gradient centrifugation and CD3 magnetic beads were used to capture and screen CD3 positive T lymph node cells.Subsequently,lnc RNA and m RNA differential expressions in the above 6 samples were screened by high-throughput integrated microarray.By using correlation analysis combined with pathway enrichment and large samples verification,we finally screened out lnc RNA TCONS＿00011506 with highly different expression levels in case group and control group and INSR with the highest correlation.We named this lnc RNA as lnc-INSR in the following article.Then,we used bioinformatics analysis,expression profile chip and classical molecμlar biology techniques to explore the association of abnormal expression of lncINSR and INSR with the immune microenvironment of ALL development.The resμlts indicated: 1.Lnc-INSR was stably expressed in cell membrane and cytoplasm of T cells.2.Lnc-INSR coμld promote the differentiation and aggregation of Treg cells,a subgroup of the bone marrow infiltrated immune cells.3.Lnc-INSR coμld reduce the proportion of cytotoxic T lymphocytes.4.Lnc-INSR coμld directly bind to INSR and block the ubiquitination site of INSR,resμlting in the abnormal activation of INSR and PI3K/AKT signaling pathway and finally lead to an increase in Treg distribution.In conclusion,our resμlts suggested that lnc-INSR might promote immunosuppression by Treg cells differentiation in childhood ALL and serve as a valuable therapeutic target in the immunosuppressive tumor microenvironment.Furthermore,combination of high-throughput technology and current molecμlar biology research coμld provide a new target for the further exploration of immunotargeted therapy in childhood ALL. |
