Insights from somatic genomics lead to novel therapeutic targets in inherited bone marrow failure syndromes: Shwachman-Diamond Syndrome as a model.

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PROJECT SUMMARY/ABSTRACT Inherited bone marrow failure syndromes are characterized by hematopoietic aplasia and predisposition to myelodysplasia. These disorders are underdiagnosed, and the only curative treatment is hematopoietic stem cell transplant. In order to understand the mechanisms that mediate bone marrow failure and clonal evolution, this proposal focuses on Shwachman-Diamond Syndrome (SDS), a bone marrow failure and MDS predisposition syndrome caused by biallelic mutations in the SBDS gene. This gene encodes a protein that regulates ribosome maturation. The SBDS protein specifically promotes formation of the mature, translationally active 80S ribosome by aiding in catalysis of removal of EIF6 from the 60S ribosomal subunit. Preliminary data presented in this proposal has identified recurrent and persistent somatic missense mutations in EIF6 and TP53 within the bone marrow of patients with SDS. The most common EIF6 mutation leads to a loss of function and abolishes EIF6 binding with the 60S ribosomal subunit and improves SDS cell fitness, identifying a novel target for SDS therapy. The central hypothesis of this proposal is that inherited bone marrow failure syndromes have decreased hematopoietic cell fitness determined by the inherited molecular defect and somatic mutations specifically rescue the underlying fitness defect or bypass cell stress pathways. The proposal addresses this hypothesis with the following specific aims: (1) Identify the hematopoietic cell of origin and hematopoietic consequences of EIF6 and TP53 somatic mutations in SDS. (2) Evaluate the disruption of the EIF6:60S interaction and decreased EIF6 protein stability in SDS. In the first aim, single cell DNA sequencing combined with DNA-barcoded immunophenotyping will be used to determine clonal architecture and a single cell genotype-phenotype of somatic mutations in the SDS bone marrow. In the second aim, rational de novo designed miniproteins will be used to interrogate EIF6:60S binding as a therapeutic strategy. Data generated from this study will inform the pathophysiology and treatment of SDS-associated bone marrow failure and can be applied to inform treatment of other bone marrow failure syndromes, the study of clonal hematopoiesis and ribosome maturation. A K08 award will provide the candidate with protected time to complete additional academic training in computational biology, somatic genomic analysis and high-throughput proteomics approaches. A detailed career development plan is proposed which will enable the candidate to attain additional scientific expertise noted above and training in grant-writing, leadership and management skills. The proposed studies will take place at the Dana- Farber/Boston Children's Hospital Cancer and Blood disorders center, an exemplary location to acquire additional training. The candidate has protected research time and strong institutional support. In addition, the candidate will have access to the Harvard Medical School-affiliated Broad Institute and Institute for Protein Innovation. These institutions are world renowned clinical and research centers that will enable the candidate to develop additional data and training to become an independent physician-scientist studying bone marrow failure.