The Roles And Mechanism Of TRIB3 Regulating Acute Promyelocytic Leukemia Dyslipidemia And Promoting MYC-Driven Lymphoma Progression

Cancer is a severe disease that seriously threatens public health.Although treatment has made great progress,tumor recurrence,metastasis and drug resistance are still major challenges in clinical treatment.TRIB3 belongs to the pseudoprotein kinases family,which has protein kinase domain but no kinase activity,its biological functions are usually performed by interacting with other critical proteins.TRIB3 participates in protein quality control by acting as stress sensor to connect metabolic stress factors to develop inflammatory diseases and tumors.Our group has explored the roles and mechanisms of TRIB3 in many types of tumors.TRIB3 interacts with various important proto-oncoprotein molecules to change cancer cell biological functions,determine the malignant degree,and even promote cancer occurrence and development,such as leukemia,colorectal cancer,melanoma,liver cancer,lung cancer and breast cancer et al.Acute promyelocytic leukemia(APL)is a subtype of leukemia and driven by oncogene PML-RAR?.TRIB3 is highly expressed in patient samples with APL and inhibits the ubiquitination and degradation of PML-RAR?,maintaining APL initiating cells self-renewal ability to promote the disease progression.The current clinical treatment is based on all-trans-retinoic acid(ATRA)combined with arsenic trioxide(As2O3).However,there are unsolved problems such as abnormal lipid metabolism and drug resistance.In the first section,we focused on exploring the mechanism of lipid metabolism disorder in patients with APL,found that TRIB3 interacted with PML-RAR? and maintained its stability.Both TRIB3 and PML-RARa hindered the binding of PPARy/RXR,promoted PPARy degradation and inhibited PPARy transcription activity,leading to the abnormal lipid metabolism of APL cells.ATRA/As2O3 can target and promote the degradation of PML-RAR?,and restore PPARy protein expression in the treatment course.However,drug therapy also increased TRIB3 expression,which destroyed the formation of PPARy/RXR dimer,inhibited PPARy activity from mediating lipid metabolism disorder.This study provides necessary theoretical support for the clinical use of lipid regulating drugs and ATRA/As2O3 combination.Lymphoma is a malignant hematologic malignancy,which is different from leukemia.Most of the patients with lymphoma in China are Non-Hodgkin's lymphoma.Lymphoma is often induced by viruses and radiating factors.The incidence rate of lymphoma is obviously increased with age.We found TRIB3 abundance is increased in non-Hodgkin's lymphoma cells,and knocked out TRIB3 can inhibit cell proliferation,sternness and tumor formation.Mechanistically,there is an interaction between TRIB3 and MYC,TRIB3 accelerated the development of lymphoma by regulating the expression of tumor oncoprotein MYC.This study will explain the mechanism of TRIB3 regulating the degradation of MYC and maintaining the stemness of lymphoma initiating cells to promote the occurrence and development of lymphoma.This study identified that the pseudokinase TRIB3 promoted the lymphoma development and detailed biological mechanism in this process.We have carried out extensive research on the biological mechanism of pseudokinase TRIB3 involved in lipid metabolism abnormalities of APL and lymphoma progression.It elaborates the mechanism of TRIB3-mediated lipid metabolism abnormality of APL at first diagnosis and after treatment.It also provides crucial theoretical support for the clinical use of lipid-lowering drugs combined with ATRA/As2O3 during the treatment of patients with APL.This thesis also reported the mechanism of TRIB3 promoting MYC-driven lymphoma progression and proposed a new strategy to interrupt TRIB3-MYC interaction for lymphoma treatment.The peptide showed anti-tumor effects in vivo and in vitro,which provided new strategies for treatment of lymphoma and a theoretical basis for anti-tumor drug development.