The Function Of Protein Synthesis In Acute Myeloid Leukemia Development And Initiation

Acute myeloid leukemia(AML)is a hematological disorder characterized by myeloid stem/progenitor cell malignant proliferation and fate arrest.With a greater understanding of cancer,treatment protocols have become more variable and personalized,but the five-year survival rate remains extremely low.Standard-based intense chemotherapy is still the primary treatment to induce remission of AML.As a result,it is still crucial to investigate the disease’s pathogenesis and potential therapeutic approaches.Due to the complexity and diversity of the genetic mutations found in patients,there is a huge amount of heterogeneity even among the same patient’s cells.Leukemia stem cells have been discovered to be distinct from normal hematopoietic stem/progenitor cells in numerous studies.For example,leukemia stem cells go through metabolic reprogramming to promote malignant growth.We focused on the difference in protein translation rate between HSPC and leukemia stem cells.Protein translation is the most elaborate and energy-intensive process in the cell.Protein translation occurs in the cytoplasm,which is bound by ribosomes on the m RNA that is transcribed and processed into the nucleus.According to the sequence carried on the m RNA,amino acids are transported by t RNA to extend the peptide chain.Translation is the cornerstone of all kinds of cell processes.By using a specific modification compound,OP-Puromycin,we examined the differential protein synthesis rate between primary mouse leukemic cells and various stem/progenitor cell populations in the normal mouse hematopoietic system in vivo.We first identified that leukemic stem cells had an extremely higher protein synthesis rate than hematopoietic stem/progenitor cells.Subsequent sh RNA screening helped us to identify an important molecule involved in the regulation of this process: RREB1.RREB1 plays an extremely important role in the progression and development of AML.Knockdown of RREB1 can severely block the progression and development of leukemia,impair intracellular protein synthesis severely,diminish the function of leukemia stem cells severely,and cause massive apoptosis of leukemia stem cells to block cell proliferation.However,knockout of RREB1 in a normal hematopoietic system did not cause stem cell damage and resulted in short-term enhancement of hematopoietic capacity monthly.This indicates that RREB1 is an ideal potential target for acute myeloid leukemia,which can not only impair the initiation and development of AML,promote the remission of patients,but also promote the patients’ hematopoietic reconstruction.We found that the main downstream target of RREB1 is a subunit of mitochondrial complex II,SDHD,which mainly mediates the effect of RREB1 in leukemia,and RREB1 regulates SDHD by directly regulating the translational efficiency,not on the transcription level.Taken together,our study has identified a novel AML stem cell characteristic with an ultra-high protein synthesis rate.RREB1 was identified as a novel regulator involved in process of protein synthesis.RREB1 knockout impairs the initiation and development of AML but promotes normal hematopoietic cell proliferation,which makes it an excellent potential target for AML targeted therapy.This work lays a solid theoretical foundation for exploring new intervention strategies and provides new ideas for the clinical treatment of AML.