The major interest of the Sieff laboratory is the molecular pathogenesis and treatment of certain inherited syndromes of bone marrow failure, particularly Diamond-Blackfan anemia (DBA), which is a congenital disease due to failure of production of red blood cells (erythrocytes) and their precursors.
Recent genetic studies have led to the identification of mutations in a ribosomal protein gene, RPS19, in about 25% of cases. Sieff and his colleagues Hanna Gazda and Alan Beggs have found evidence for involvement of at least 9 other genes, and experiments focus on genetic studies to identify other DBA genes. Surprisingly, GATA1, an essential erythroid transcription factor, was found to be mutated in a small proportion of patients without RP gene mutations.
Other laboratory studies focus on depletion of ribosomal proteins in mouse fetal liver cells to determine why insufficiency of ribosomal proteins, which is characteristic of patients with DBA, leads to red cell failure. In acquired aplastic anemia, studies focus on making, characterizing and comparing induced pluripotent stem cells derived from skin and bone marrow cells.
Clinical studies in bone marrow failure patients include a study to investigate the safety and efficacy of danazol in patients with Fanconi anemia and Dyskeratosis congenita. This study has opened and is recruiting patients.
Aplastic anemia is an acquired failure of blood cell production. The underlying cause is not well understood, and laboratory studies focus on using novel technology to make induced pluripotent stem cells from both fibroblasts and blood forming cells of patients with severe aplastic anemia, to compare their genetic profiles.
About Colin Sieff
Colin Sieff received his MB.BCh. from the University of the Witwaterswand, Johannesburg, South Africa, in 1968. He trained in hematology at The Royal Marsden, St. George's Hospital and The Royal Free Hospital, and in pediatric hematology at the Hospital for Sick Children in London. He was named Claudia Adams Barr Program Investigator in Innovative Basic Cancer Research at Dana-Farber Cancer Institute in 1999. He directs the bone marrow failure program.
- Gazda H, Lipton JM, Willig TN, Ball S, Niemeyer CM, Tchernia G, Mohandas N, Daly MJ, Ploszynska A, Orfali KA, Vlachos A, Glader BE, Rokicka-Milewska R, Ohara A, Baker D, Pospisilova D, Webber A, Viskochil DH, Nathan DG, Beggs AH, Sieff CA. Evidence for linkage of familial Diamond-Blackfan anemia to chromosome 8p23.3-p22 and for non-19q non-8p disease. Blood 2001; 97: 2145-2150.
- Gazda HT, Zhong R, Long L, Niewiadomska A, Lipton JM, Ploszynska A, Zaucha JM, Vlachos A, Atsidaftos E, Viskochil DH, Niemeyer CM, Meerpohl JJ, Rokicka-Milewska R, Pospisilova D, Wiktor-Jedrzejczak W, Nathan DG, Beggs AH, and Colin A Sieff. RNA and protein evidence for haploinsufficiency in Diamond-Blackfan anemia patients with RPS19 mutations. British Journal of Haematology; 127:105-13, 2004.
- Ebert BL, Lee MM, Pretz JL, Subramanian A, Mak R, Golub TR, Sieff CA. An RNA interference model of RPS19 deficiency in Diamond Blackfan Anemia recapitulates defective hematopoiesis and rescue by dexamethasone: identification of dexamethasone responsive genes by microarray. Blood; 105: 4620-4626, 2005.
- Gazda HT, Grabowska A, Merida-Long LB, Latawiec E, Schneider HE, Lipton JM, Vlachos A, Atsidaftos E, Ball SE, Orfali KA, Niewiadomska E, Da Costa L, Tchernia G, Niemeyer C, Meerpohl JJ, Stahl J, Schratt G, Glader B, Backer K, Wong C, Nathan DG, Beggs AH and Sieff CA. Ribosomal Protein S24 Gene is Mutated in Diamond-Blackfan Anemia. Am J Hum Genet: 79:1110-1118, 2006.
- Gazda HT, Sieff CA. Recent insights into the pathogenesis of Diamond-Blackfan anaemia. Br J Haematol. 135: 149-57. 2006
- Gazda HT, Sheen MR, Vlachos A, Choesmel V, O'Donohue MF, Schneider H, Darras N, Hasman C, Sieff CA, Newburger PE, Ball SE, Niewiadomska E, Matysiak M, Zaucha JM, Glader B, Niemeyer C, Meerpohl JJ, Atsidaftos E, Lipton JM, Gleizes PE, Beggs AH. Ribosomal protein L5 and l11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet: 83: 769-80, 2008.
- Sieff CA, Jang J, Merida-Long L, Lodish HF. Pathogenesis of the Erythroid Failure in Diamond Blackfan Anemia Brit J Haematol: 148: 611-22, 2010.
- Sankaran, Vijay G; Ghazvinian, Roxanne; Do, Ron; Thiru, Prathapan; Vergilio, Jo-Anne A; Beggs, Alan H; Sieff, Colin A; Orkin, Stuart H; Nathan, David G; Lander, Eric S; Gazda, Hanna T. Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia. The Journal of clinical investigation. 2012 122(7):2439-43