Rare disorders offer unique insights into global pathologic mechanisms affecting the general population. The study of inherited bone marrow failure syndromes has elucidated novel molecular pathways underlying hematopoietic aplasia and cancer predisposition. Genetic mutations affecting ribosome biogenesis underlie several inherited bone marrow failure syndromes: Diamond-Blackfan anemia, dyskeratosis congenita, cartilage-hair hypoplasia, and Shwachman-Diamond syndrome. More recently, acquired haploinsufficiency of the RPS14 gene has been associated with the 5q- myelodysplastic syndrome. It is currently unclear how ribosomal disorders result in marrow failure and leukemogenesis. To investigate the role of ribosomes in hematopoiesis and malignancy, we focused on Shwachman- Diamond syndrome, an autosomal recessively inherited marrow failure syndrome associated with mutations in the highly conserved SBDS gene. The precise molecular functions of SBDS in ribosomal pathways remain to be defined. Based upon our prior studies, we propose the following specific aims: 1. Define the functional domains of the SBDS protein, 2. Investigate the molecular mechanisms whereby SBDS promotes ribosome biogenesis, and 3. Elucidate the role of SBDS in hematopoiesis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Hematopoiesis Study Section (HP)
Program Officer
Qasba, Pankaj
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Fred Hutchinson Cancer Research Center
United States
Zip Code
Stumpff, Jason; Ghule, Prachi N; Shimamura, Akiko et al. (2014) Spindle microtubule dysfunction and cancer predisposition. J Cell Physiol 229:1881-3
Ruggero, Davide; Shimamura, Akiko (2014) Marrow failure: a window into ribosome biology. Blood 124:2784-92
Myers, Kasiani C; Bolyard, Audrey Anna; Otto, Barbara et al. (2014) Variable clinical presentation of Shwachman-Diamond syndrome: update from the North American Shwachman-Diamond Syndrome Registry. J Pediatr 164:866-70
Tulpule, Asmin; Kelley, James M; Lensch, M William et al. (2013) Pluripotent stem cell models of Shwachman-Diamond syndrome reveal a common mechanism for pancreatic and hematopoietic dysfunction. Cell Stem Cell 12:727-36
Burwick, Nicholas; Shimamura, Akiko; Liu, Johnson M (2011) Non-Diamond Blackfan anemia disorders of ribosome function: Shwachman Diamond syndrome and 5q- syndrome. Semin Hematol 48:136-43
Wong, Trisha E; Calicchio, Monica L; Fleming, Mark D et al. (2010) SBDS protein expression patterns in the bone marrow. Pediatr Blood Cancer 55:546-9
Burroughs, Lauri; Woolfrey, Ann; Shimamura, Akiko (2009) Shwachman-Diamond syndrome: a review of the clinical presentation, molecular pathogenesis, diagnosis, and treatment. Hematol Oncol Clin North Am 23:233-48
Austin, Karyn M; Gupta, Mohan L; Coats, Scott A et al. (2008) Mitotic spindle destabilization and genomic instability in Shwachman-Diamond syndrome. J Clin Invest 118:1511-8
Ganapathi, Karthik A; Austin, Karyn M; Lee, Chung-Sheng et al. (2007) The human Shwachman-Diamond syndrome protein, SBDS, associates with ribosomal RNA. Blood 110:1458-65
Austin, Karyn M; Leary, Rebecca J; Shimamura, Akiko (2005) The Shwachman-Diamond SBDS protein localizes to the nucleolus. Blood 106:1253-8