Research Abstract:
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 more specific treatment. BMF is the diminished function of the bone marrow leading to inadequate blood cell production. Interestingly, investigation of inherited forms of bone marrow failure revealed that not genes specific for blood cell production are mutated in these patients but rather genes that are important for the growth of every cell, furthermore the pathway affected play a central role in regenerative medicine and cancer biology. 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 PIGA gene essential for the biosynthesis of glycosyl phosphatidylinositol (GPI) anchor molecules. We investigate the consequences on hematopoiesis, leukemogenesis, and immune response.
DC is inherited. DC patients have in addition to BMF abnormalities of the skin, nails, and buccal mucosa as well a predisposition to develop cancer. DC patients have excessively short telomeres. Our studies are to characterize the pathway of telomere shortening and to identify the mechanisms that lead to BMF and cancer.
The most recent project in our laboratory is to study role of 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, growth retardation and other congenital anomalies. Mutations in the ribosomal protein RPS19 are found in about 25% of patients, suggesting that ribosomal biogenesis is altered in DBA. Our studies are to characterize the defect(s) in ribosome biogenesis and to identify the pathways leading to red cell aplasia.
Selected Publications:
Gu BW, Gu BW, Bessler M, Mason PJ. A pathogenic dyskerin mutation impairs proliferation and activates a DNA damage response independent of telomere length in mice. PNAS. 2008 Jul 22;105(29):10173-8.
Robledo S, Idol RA, Crimmins DL, Ladenson JH, Mason PJ, Bessler M. The role of human ribosomal proteins in the maturation of rRNA and ribosome production. RNA 2008 Sep;14(9):1918-29. PMID: 18697920.
Du HY, Pumbo E, Manley P, Field JJ. Bayliss SJ, Wilson DB, Mason PJ, Bessler M. Complex inheritance pattern of dyskeratosis congenita in two families with two different mutations in the telomerase reverse transcriptase gene. Blood 2008 Feb 1;111(3):1128-30.
Mason, PJ, Bessler M. Dark skin mutation shed light on inherited anemia. Nature Genetics 2008 Aug;40(8):931-932.
Goldman F, Bouharich R, Kulkarni S, Freeman S, Du HY, Harrington L, Mason JP, Londono-Vallejo A, Bessler M. The effect of TERC haploinsufficiency on the inheritance of telomere length. PNAS 2005 102(47):17119-17124.
Last Updated: 08/10/2009 |