BMI1 Promotes Erythropoiesis Through Regulating Ribosome Biogenesis
Authors: Gao Rui , Chen Sisi , Kobayashi Michihiro , Yoder Mervin C. , Kapur Reuben , Zhu Xiaofan , Liu Yan 
Published: October 2019

Abstract
Diamond-Blackfan anemia (DBA) is a rare congenital bone marrow failure syndrome of childhood manifested as macrocytic anemia with insufficient erythroid precursors in the bone marrow. Within the decade following the demonstration that mutations in the ribosomal protein gene RPS19 can lead to DBA, this disease has become a paradigm for an emerging group of pathologies (ribosomopathies) linked to defects in ribosome biogenesis. Mutations in ribosomal protein genes impair ribosome biogenesis, resulting in activation of the p53 tumor suppressor pathway, cell cycle arrest and defective erythropoiesis. While mutations in ribosomal protein genes have been found in 50-60% of DBA patients, genetic abnormalities in the remaining patients are largely unknown. Despite improvements in our understanding of the pathophysiology of DBA, the molecular basis for selective impairment of the erythroid lineage in this disorder is not understood. In particular, how ribosome biogenesis is regulated in erythroid precursors remains elusive. Our laboratory has been investigating the role of Polycomb group protein Bmi1 in regulating hematopoietic stem cell (HSC) self-renewal and lineage commitment. Recently, we found that Bmi1 is a critical downstream target of AKT signaling and AKT-mediated phosphorylation of Bmi1 inhibits HSC self-renewal (Liu et al., Science Signaling, 2012). Upon more detailed analysis of the hematopoietic phenotype of the Bmi1 knockout mice, we have observed that these mice develop macrocytic anemia and show delayed recovery following phenylhydrazine (PHZ)-induced hemolytic anemia. This phenotype suggests defective erythropoiesis and we identified that loss of Bmi1 expression results in a block in erythroid differentiation and decreased erythroid colony formation. Gene expression profiling indicated that multiple ribosomal protein genes were downregulated in Bmi1 null erythroid precursors. Moreover, we discovered that the p53 pathway is activated in Bmi1 null erythroid progenitor cells and genetic inhibition of p53 activity rescued the erythroid defects in the Bmi1 deficient mice. Thus, Bmi1 null mice recapitulate many critical features of human DBA. Furthermore, we demonstrated that BMI1 plays a critical role in human erythropoiesis as knockdown of BMI1 in human CD34+ cells decreases ribosomal protein gene expression, activates the p53 pathway, and blocks erythroid differentiation. Importantly, we observed that BMI1 expression is downregulated in bone marrow cells from some DBA patients. Thus, BMI1 plays a critical role in regulating ribosome biogenesis in erythroid precursors and BMI1 deficiency may contribute to the pathogenesis of DBA. Understanding how BMI1 regulates ribosome biogenesis and erythroid development will provide novel insight into the processes by which BMI1 and ribosomopathies contribute to the pathogenesis of DBA and potentially new targets for therapeutic intervention.

Disclosures:
No relevant conflicts of interest to declare.