1R01 DK115536-01 revised Inherited bone marrow failure disorders (BMFDs) represent a distinct category of hematopoietic disorders that are driven by genetic mutation. Within these disorders, a distinct set of genes has already been identified that contribute to a sub-set of BMFDs known as ribosomopathies. Ribosomopathies harbor mutation to genes playing a critical role in ribosomal processing and ribosome biogenesis. We previously established the DKC1 gene as a ribosomopathy gene through its ability to regulate proper translation as a result of its function to convert uridine residues on ribosomal RNAs (rRNAs) to pseudouridine. Exciting, preliminary data from our lab now demonstrates that another post-transcriptional modification of rRNAs, 2?-O-methylation (2?-O-Me), also contribute to proper regulation of ribosome function. Our data reveal that specific C/D-box small nucleolar RNAs (snoRNAs) controls proper IRES-dependent translation of major cell cycle and apoptosis genes. In vivo, disruption of 2?-O-Me in adult mouse hematopoietic stem cell (HSC) compartment results in features characteristic of ribosomopathies such as defects in stem cell maintenance due to exit from quiescence, apoptosis, and myelodysplastic bone marrow failure. Importantly, we identify novel germ line mutations dyskeratosis congenita (DC) patients related to function of C/D box snoRNAs. Thus, our preliminary findings provide direct genetic evidence for the critical role ribosome specialization through rRNA 2?-O-Me, as well as in the pathogenesis of multiple disease states through aberrant HSC and ribosome function. In order to better understand the role and function 2?-O-Me, we propose to (1) study the molecular and cellular pathways that are impacted by 2?-O-Me and which contribute to the process of bone marrow failure, (2) determine the in vivo significance of normal ribosome function for hematopoiesis, and of novel DC mutations identified through development of genetically engineered mouse models, and (3) evaluate the extent to which genes involved in the biochemical complexes that catalyzes 2?-O-Me may be altered in BMFDs, and to determine if additional novel pathogenic mutations targeting the process of rRNA methylation, including snoRNAs, exist in BMFDs. Together these data will further facilitate our understanding of ribosomopathies, and help uncover how essential regulation of the ribosome, through rRNA modification, contributes to normal and aberrant hematopoiesis.

Public Health Relevance

Ribosomopathies and related bone marrow failure disorders are frequently cased by mutation to genes involved in ribosome processing and ribosome biogenesis. We now identify aberrant 2'-O-methylation (2'-O- Me) of rRNAs as an additional novel mechanism promoting bone marrow failure (BMF), characterize NPM1 as a mediator of 2'-O-Me and ribosomal function, and identify NPM1 mutations in the ribosomopathy dyskeratosis congenita. This proposal will determine the mechanisms by which aberrant 2'-O-Me and NPM1 deficiency contribute to BMF, we will generate novel dyskeratosis congenita in vivo models to study the role of ribosomal alteration in hematopoiesis and BMF, and determine the existence of additional genes and mutations involved in 2'-O-Me control and the pathogenesis of BMF related disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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Molecular and Cellular Hematology Study Section (MCH)
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Roy, Cindy
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Beth Israel Deaconess Medical Center
United States
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