The long-term goal of our research is to delineate the molecular events leading to bone marrow failure (BMF) and to identify new biomarkers for a more accurate diagnosis and a more specific treatment for patients with bone marrow failure. BMF is the diminished function of the bone marrow leading to inadequate blood cell production. BMF may affect all three major blood cell lineages (red blood cells, white blood cells, and platelets), although one lineage may be disproportionately affected. BMF is heterogeneous in its pathogenesis. Most cases of BMF are classified as idiopathic; relatively few cases are due to recognizable genetic diseases. Currently we are studying three BMF syndromes: Paroxysmal Nocturnal Hemoglobinuria (PNH), Dyskeratosis Congenita (DC), and Diamond Blackfan Anemia (DBA).
PNH is due to the expansion of a hematopoietic progenitor cell that has acquired a mutation in the X-linked PIGA gene. PIGA is essential for the biosynthesis of glycosyl phosphatidylinositol (GPI) anchor molecules. Blood cells from patients with PNH are therefore deficient in all GPI-anchored proteins. Our studies are to identify the growth/survival advantage that leads to the clonal expansion of mutant progenitor cells. We are interested in the mechanisms of thrombosis, which is the major cause of death in patients with PNH and we investigate the consequences caused by the lack of GPI-linked proteins on hematopoiesis, leukemogenesis, and immune response.
DC, in contrast to PNH, is inherited. Patients have in addition to bone marrow failure abnormalities of the skin, nails, and buccal mucosa. Patients with this disease have an increased risk to develop cancer. There is an X-linked, an autosomal recessive, and an autosomal dominant form of the disease, suggesting that several genes might be affected that participate in the same biological pathway. Patients with DC have excessively short telomeres. Our studies are to characterize the pathway of excessive telomere shortening in these patients and to understand the mechanisms that lead to bone marrow failure and cancer predisposition.
The most recent project in our laboratory is to study role of defective ribosomal biogenesis in the pathogenesis of red cell aplasia in patients with DBA. DBA is an inherited BMF syndrome, characterized by anemia, absence of red cell precursors in the bone marrow, growth retardation and other congenital anomalies, which vary. Mutations in the ribosomal protein RPS19 are found in about one fourth of DBA patients, suggesting that ribosomal biogenesis is altered in patients with this disease. Our studies are to characterize the defect(s) in ribosome biogenesis and to identify the pathways leading to red cell aplasia in patients with DBA.
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Proposed model of the pathogenesis of bone marrow failure in patients with DC
In this model excessively short telomeres are the underlying cause of clinical manifestations in patients with DC. Mutations in TERC or TERT affect the activity of telomerase. Mutations in DKC1 destabilize TERC and/or retard ribosome biogenesis. As telomeres get shorter there is an increase in genomic instability leading eventually to a cell crisis, cell cycle arrest, and cell death. Rare cells that can maintain telomere integrity emerge from the crisis as potentially malignant cells.
From: Mason PJ, Wilson DB, Bessler M
Dyskeratosis congenita -- a disease of dysfunctional telomere maintenance.
Curr Mol Med 2005 Mar;5(2):159-70
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