The Mechanism Of TRIB3 Promoting APL Progression

Acute promyelocytic leukemia(APL)is a highly malignant type of hematopoietic system cancers with bad prognosis,which accounts for approximately 10%of adult acute myeloid leukemia(AML).AML causes bleeding and diffuse intravascular coagulation(DIC),especially during chemotherapy,which lead to patients’early death.It was found that chromosomal translocation of the specific T(15,17)occurs in more than 90%of AML patients,which leads to the fusion of the 15th chromosome promyelocytic leukemia(PML)gene and the 17th chromosome Retinoic acid receptor(RARa)gene.The fusion gene produces oncoprotein PML-RARa,which antagonizes myeloid differentiation,promotes APL-initiating cell self-renewal and triggers the onset of APL.Currently,combined all-trans retinoic acid(ATRA)with arsenic trioxide(AS2O3)or chemotherapy has dramatically improved the prognosis of APL patients.However,the first-line drugs may cause serious adverse events including systemic infection and secondary leukemia.Moreover,some APL patients fail to respond to the therapy targeting PML-RARa or relapse after a complete remission,which prompt researchers to further investigate the pathogenesis of APL and find potential treatment drugs.Recent studies have indicated that 3 members of the pseudokinase Tribbles Homolog family,TRIB1,TRIB2 and TRIB3,act as stress sensors in response to a diverse range of metabolic stressors,and are involved in chronic inflammatory,and tumor development and progression.Tribl and Trib2,as proto-oncogene,can induce AML,and the related mechanism has been proved,but much less is known about the role of Trib3 in the pathogenesis of AML.We previously reported that TRIB3 not only promotes the transforming growth factor(TGF)-β1-mediated tumor invasion and migration,but also links the risk factors of metabolism and tumor progression.In this study,we found that TRIB3 was elevated in human primary leukemia cells.Also,the enhanced TRIB3 expression associates positively with APL progression and therapeutic resistance.Using triple-transgenic mice,we tested the hypothesis that elevated TRIB3 expression contributes to APL pathogenesis.We found that Trib3 knockin promoted,whereas Trib3 knockout suppressed,Pml-Rara-driven APL.Here we report that TRIB3 represses PML nuclear body assembly,p53-mediated senescence,cell differentiation and supports cellular self-renewal.Taken together,these data indicate that high TRIB3 expression promotes PML-RARa-Driven APL.In recent years,protein quality control has been one of the hot topics in cancer.The dysfunction of protein quality control,such as the defective autophagy or ubiquitin proteasome system(UPS),can result in the accumulation of cancer-promoting factors.Recently,we found that TRIB3 affected the expression of tumor-promoting factors via regulating the activation of autophagy and UPS.Furthermore,we report that the elevated TRIB3 expression promotes APL by interacting with PML-RARa and suppressing the sumoylation,ubiquitylation and degradation of PML-RARa,which can sustain the functions of oncoprotein PML-RARa.After identifying the domain and key amino acid sites of PML-RARa/TRIB3 or PML/TRIB3 interaction,we found that TRIB3 mainly interacts with the sumoylation motifs of PML-RARa/PML.Moreover,these interactions play a crucial role in promoting APL progression.Currently,targeting protein-protein interaction has become a novel hot filed in drug discovery.Hence,targeting TRIB3 or disturbing TRIB3/PML-RARα interaction may provide insight or new therapeutic options for APL treatment.