The inherited bone marrow failure and myelodysplastic syndromes (iBMF/MDS) are a heterogeneous group of disorders that are characterized by impaired hematopoiesis and a propensity to progress to leukemia. Despite recent advances in the field, a significant percentage of patients presenting with inherited marrow failure or MDS do not fall into the known diagnostic categories and remain idiopathic. Since many of these genetic syndromes entail specific management and treatment considerations that differ significantly from standard therapies used for acquired marrow failure/MDS, accurate diagnosis is essential. This is a resource development and gene discovery grant investigating iBMF/MDS to characterize their phenotypic spectrum, to develop novel imaging modalities for bone marrow pathology, and to gain insights into the genetic and molecular mechanisms regulating hematopoiesis and marrow failure. We will apply cutting edge genomics approaches to samples from comprehensively phenotyped children and adults to identify new genes responsible for iBMF/MDS. This project will also investigate the clinical and biological consequences of somatically acquired genetic mutations on disease progression and prognosis in iBMF/MDS and determine the similarities or differences in genetic landscapes between inherited versus acquired marrow failure/MDS. We will also interrogate seemingly sporadic marrow failure or MDS presenting in the general population for cryptic presentations of inherited disorders. Resources generated for the broader clinical and scientific communities will include high-throughput multiplexed gene analysis platforms for iBMF/MDS, evidence- based algorithms for the diagnostic workup and management of iBMF/MDS, centralized hematopathology review, and comprehensively clinically annotated biological samples for further investigation. This project should yield new insights into blood cell development and the molecular pathogenesis of marrow failure and MDS;will advance the development of new diagnostic tests, therapies and biomarkers for marrow failure and MDS;will provide clinical resources forthe hematology community;and will provide new tools and methods for future studies ofthe molecular pathways regulating hematopoiesis.
This project focuses on clinical, pathological, genetic, and molecular studies of bone marrow failure and myelodysplastic syndromes (MDS). Identification of the molecular causes of these disorders informs medical therapy for these disorders. This project will advance our understanding of the mechanisms of blood cell production with the goal of developing new diagnostic tests and treatments for marrow failure and MDS.
|Seo, Aaron; Ben-Harosh, Miri; Sirin, Mehtap et al. (2017) Bone marrow failure unresponsive to bone marrow transplant is caused by mutations in thrombopoietin. Blood 130:875-880|
|Kennedy, James A; Ebert, Benjamin L (2017) Clinical Implications of Genetic Mutations in Myelodysplastic Syndrome. J Clin Oncol 35:968-974|
|Godley, Lucy A; Shimamura, Akiko (2017) Genetic predisposition to hematologic malignancies: management and surveillance. Blood 130:424-432|
|Mamrak, Nicholas E; Shimamura, Akiko; Howlett, Niall G (2017) Recent discoveries in the molecular pathogenesis of the inherited bone marrow failure syndrome Fanconi anemia. Blood Rev 31:93-99|
|Lindsley, R Coleman; Saber, Wael; Mar, Brenton G et al. (2017) Prognostic Mutations in Myelodysplastic Syndrome after Stem-Cell Transplantation. N Engl J Med 376:536-547|
|Furutani, Elissa; Shimamura, Akiko (2017) Germline Genetic Predisposition to Hematologic Malignancy. J Clin Oncol 35:1018-1028|
|Hock, Hanno; Shimamura, Akiko (2017) ETV6 in hematopoiesis and leukemia predisposition. Semin Hematol 54:98-104|
|Sperling, Adam S; Gibson, Christopher J; Ebert, Benjamin L (2017) The genetics of myelodysplastic syndrome: from clonal haematopoiesis to secondary leukaemia. Nat Rev Cancer 17:5-19|
|Gibson, Christopher J; Lindsley, R Coleman; Tchekmedyian, Vatche et al. (2017) Clonal Hematopoiesis Associated With Adverse Outcomes After Autologous Stem-Cell Transplantation for Lymphoma. J Clin Oncol 35:1598-1605|
|Khincha, Payal P; Bertuch, Alison A; Agarwal, Suneet et al. (2017) Pulmonary arteriovenous malformations: an uncharacterised phenotype of dyskeratosis congenita and related telomere biology disorders. Eur Respir J 49:|
Showing the most recent 10 out of 29 publications