YBX1 Is Required For Maintaining Myeloid Leukemia Cell Survival By Stabilizing BCL2

Acute myeloid leukemia(AML)is an aggressive hematological malignancy caused by genetic or epigenetic changes such as gene mutations or chromosomal translocations.These changes lead to differentiation disorders and malignant proliferation of myeloid progenitor cells.Acute myeloid leukemia is the most common acute leukemia in adults.With the advancement of treatment options,the complete remission rate of AML has improved significantly,but its five-year overall survival rate is still low.Therefore,studying the pathogenesis of AML and exploring new therapeutic targets are the key scientific issues in this field.Recently,the study of genetic and epigenetic changes in the occurrence and development of AML has been more in-depth explored.However,post-transcriptional regulation affects the occurrence and development of AML is still poorly understood.RNA binding proteins(RBPs)are proteins that can bind double-stranded or single-stranded RNA,and are widely involved in post-transcriptional regulation.It is currently known that RBPs are involved in RNA transcription and post-transcriptional regulation,such as alternative splicing,RNA modification,nuclear export,localization,stability,and degradation,thereby affecting the fate of RNA.More and more studies have shown that RBPs participate in the regulation of cell homeostasis under normal physiological and pathological conditions,and play an important role in tumorigenesis.Although studies in recent years have gradually revealed the role of some RBPs in normal hematopoietic and hematological malignancies,the role of RBPs in the functional homeostasis of leukemia cells remains to be studied.In this study,we found that YBX1 regulates the fate determination of m~6A modified RNA,and plays a key role in AML development and the maintenance of the functional homeostasis of leukemia cells.Through a comprehensive analysis of the expression levels of 1068 RBPs m RNA in AML patient cells,we found that YBX1 is significantly highly expressed in myeloid leukemia cells.YBX1 is a multifunctional RNA/DNA binding protein with a conserved cold shock domain(CSD),and is involved in cell apoptosis,cell proliferation,m RNA splicing,translation,DNA damage repair,differentiation and physiological processes such as stress response.But its role in leukemia is unclear.Thus,we further used sh RNA interference technology to knock down YBX1 in leukemia cell lines to study its effect on the biological characteristics of leukemia.We found that knocking down YBX1 expression caused myeloid leukemia cell growth inhibition,decreased clonal formation,and promoted leukemia cell differentiation and apoptosis.Further,using the PDX model,we found that knocking down YBX1 significantly inhibit leukemia stem cells transplantation ability in immunodeficient NSG mice,which indicates that inhibiting the expression of YBX1impairs the function of leukemia stem cells.Importantly,we used Ybx1 conditional knockout mice to explore the role of Ybx1 in leukemia.And we found that the deletion of Ybx1 significantly prolong the survival of leukemia mice without affecting normal hematopoiesis.In terms of mechanism,we found that YBX1 mainly interacts with IGF2BPs through its CSD domain to recognize and promote the stability of m~6A-modified apoptosis-related genes MYC and BCL2 m RNA,thereby promoting the survival of myeloid leukemia cells.Therefore,our research clarified the role and mechanism of YBX1 in specifically regulating AML,which reveals the new function and mechanism of YBX1 in blood physiology and pathology.Meanwhile,this research provides a potential target for specifically targeting leukemia,lays a theoretical foundation for exploring new intervention strategy,and has important application value for clinical treatment of leukemia.