Diamond Blackfan Anemia (DBA) is a congenital syndrome characterized by decreased production of red blood cells and developmental abnormalities. This syndrome is caused by mutations in ribosomal genes (RPs), most frequently in RPS19, RPL11, and RPL5. Previously, we created RPS19 deficient zebrafish using morpholinos and demonstrated that p53 family members mediate the effects of RPS19 deficiency on development and hematopoiesis through upregulation of p53-related proteins. In this study, we found that RPL11 mutations, similar to RPS19 deficiency, leads to dysregulation of p53, its related family members, and downstream signaling pathways in zebrafish. Expression of both total p53 and Δ113Np53 is strongly upregulated in mutants with more modest upregulation of ΔNp63. The p53 protein also induced p21 and G1 cyclin expression, which resulted in cell cycle arrest. The pro-apoptotic genes, puma and bax, were also upregulated. We observed that the expression of several genes involved in hematopoiesis was altered, for example, globin gene expression was decreased. The ΔNp63 protein, which increases expression of adenosine deaminase (ADA) and is upregulated in >70% of DBA patients, was also upregulated in RPL11 zebrafish mutants. Interestingly, we also observed increased expression of the proto-oncogenes c-fos, c-jun, and c-myc in RPL11 mutants. Increased expression of proto-oncogenes may contribute to the mechanisms of transcriptional activation by p53 family members in response to ribosomal protein deficiency. Furthermore, aberrant expression of oncogenes could provide a possible mechanism for the increased risk of malignancies in DBA patients. We propose that the zebrafish is a model system to study developmental and hematologic defects in addition to signaling pathways in the pathogenesis of DBA.

Disclosures: No relevant conflicts of interest to declare.

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