Research Overview

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.

Research Background

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.

 

Publications

  1. A Grammastola spatulata mechanotoxin-4 (GsMTx4)-sensitive cation channel mediates increased cation permeability in human hereditary spherocytosis of multiple genetic etiologies. Haematologica. 2021 10 01; 106(10):2759-2762. View Abstract
  2. L-leucine improves anemia and growth in patients with transfusion-dependent Diamond-Blackfan anemia: Results from a multicenter pilot phase I/II study from the Diamond-Blackfan Anemia Registry. Pediatr Blood Cancer. 2020 12; 67(12):e28748. View Abstract
  3. TGFß signaling underlies hematopoietic dysfunction and bone marrow failure in Shwachman-Diamond Syndrome. J Clin Invest. 2019 06 18; 129(9):3821-3826. View Abstract
  4. Aberrant splicing contributes to severe a-spectrin-linked congenital hemolytic anemia. J Clin Invest. 2019 04 30; 129(7):2878-2887. View Abstract
  5. A Successful Collaborative Approach to the Perioperative Management After Hip Arthroscopy of a Patient with Heterozygous Prothrombin G20210A Mutation: A Case Report. JBJS Case Connect. 2019 Apr-Jun; 9(2):e0376. View Abstract
  6. The Genetic Landscape of Diamond-Blackfan Anemia. Am J Hum Genet. 2019 Feb 07; 104(2):356. View Abstract
  7. The Genetic Landscape of Diamond-Blackfan Anemia. Am J Hum Genet. 2018 12 06; 103(6):930-947. View Abstract
  8. Acquired and Inherited Bone Marrow Failure Syndromes. Hematol Oncol Clin North Am. 2018 08; 32(4):xiii-xiv. View Abstract
  9. Introduction to Acquired and Inherited Bone Marrow Failure. Hematol Oncol Clin North Am. 2018 08; 32(4):569-580. View Abstract
  10. The phenotypic spectrum of germline YARS2 variants: from isolated sideroblastic anemia to mitochondrial myopathy, lactic acidosis and sideroblastic anemia 2. Haematologica. 2018 12; 103(12):2008-2015. View Abstract
  11. Critical Issues in Diamond-Blackfan Anemia and Prospects for Novel Treatment. Hematol Oncol Clin North Am. 2018 Aug; 32(4):701-712. View Abstract
  12. Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors. Sci Transl Med. 2017 02 08; 9(376). View Abstract
  13. Characteristic peripheral blood smear findings in disorders of cobalamin metabolism. Blood. 2016 11 24; 128(21):2584. View Abstract
  14. A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nat Genet. 2016 Jan; 48(1):74-8. View Abstract
  15. Altered translation of GATA1 in Diamond-Blackfan anemia. Nat Med. 2014 Jul; 20(7):748-53. View Abstract
  16. Diagnosis and treatment of pediatric acquired aplastic anemia (AAA): an initial survey of the North American Pediatric Aplastic Anemia Consortium (NAPAAC). Pediatr Blood Cancer. 2014 May; 61(5):869-74. View Abstract
  17. Novel deletion of RPL15 identified by array-comparative genomic hybridization in Diamond-Blackfan anemia. Hum Genet. 2013 Nov; 132(11):1265-74. View Abstract
  18. Exome sequencing identifies GATA1 mutations resulting in Diamond-Blackfan anemia. J Clin Invest. 2012 Jul; 122(7):2439-43. View Abstract
  19. Frameshift mutation in p53 regulator RPL26 is associated with multiple physical abnormalities and a specific pre-ribosomal RNA processing defect in diamond-blackfan anemia. Hum Mutat. 2012 Jul; 33(7):1037-44. View Abstract
  20. Genetic variants in the noncoding region of RPS19 gene in Diamond-Blackfan anemia: potential implications for phenotypic heterogeneity. Am J Hematol. 2010 Feb; 85(2):111-6. View Abstract
  21. Ribosomal protein genes RPS10 and RPS26 are commonly mutated in Diamond-Blackfan anemia. Am J Hum Genet. 2010 Feb 12; 86(2):222-8. View Abstract
  22. Pathogenesis of the erythroid failure in Diamond Blackfan anaemia. Br J Haematol. 2010 Feb; 148(4):611-22. View Abstract
  23. Ribosomal protein L5 and L11 mutations are associated with cleft palate and abnormal thumbs in Diamond-Blackfan anemia patients. Am J Hum Genet. 2008 Dec; 83(6):769-80. View Abstract
  24. Abnormalities of the large ribosomal subunit protein, Rpl35a, in Diamond-Blackfan anemia. Blood. 2008 Sep 01; 112(5):1582-92. View Abstract
  25. Ribosomal protein S24 gene is mutated in Diamond-Blackfan anemia. Am J Hum Genet. 2006 Dec; 79(6):1110-8. View Abstract
  26. Recent insights into the pathogenesis of Diamond-Blackfan anaemia. Br J Haematol. 2006 Oct; 135(2):149-57. View Abstract
  27. Defective ribosomal protein gene expression alters transcription, translation, apoptosis, and oncogenic pathways in Diamond-Blackfan anemia. Stem Cells. 2006 Sep; 24(9):2034-44. View Abstract
  28. Investigation of a putative role for FLVCR, a cytoplasmic heme exporter, in Diamond-Blackfan anemia. Blood Cells Mol Dis. 2005 Sep-Oct; 35(2):189-92. View Abstract
  29. 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. 2005 Jun 15; 105(12):4620-6. View Abstract
  30. Accumulation of an intron-retained mRNA for granulocyte macrophage-colony stimulating factor receptor common beta chain in neutrophils of myelodysplastic syndromes. J Leukoc Biol. 2005 May; 77(5):811-9. View Abstract
  31. RNA and protein evidence for haplo-insufficiency in Diamond-Blackfan anaemia patients with RPS19 mutations. Br J Haematol. 2004 Oct; 127(1):105-13. View Abstract
  32. Evidence for linkage of familial Diamond-Blackfan anemia to chromosome 8p23.3-p22 and for non-19q non-8p disease. Blood. 2001 Apr 01; 97(7):2145-50. View Abstract
  33. Congenital bone marrow failure syndromes. Br J Haematol. 2000 Oct; 111(1):30-42. View Abstract
  34. Diamond-Blackfan anemia. Curr Opin Hematol. 2000 Mar; 7(2):85-94. View Abstract
  35. Gene dose-dependent control of hematopoiesis and hematologic tumor suppression by CBP. Genes Dev. 2000 Feb 01; 14(3):272-7. View Abstract
  36. Maturation and lineage-specific expression of the coxsackie and adenovirus receptor in hematopoietic cells. Stem Cells. 2000; 18(3):176-82. View Abstract
  37. Essential role for the p55 tumor necrosis factor receptor in regulating hematopoiesis at a stem cell level. J Exp Med. 1999 Nov 15; 190(10):1493-504. View Abstract
  38. Pure red-cell aplasia. N Engl J Med. 1999 Jun 24; 340(25):2004; author reply 2005. View Abstract
  39. One-day ex vivo culture allows effective gene transfer into human nonobese diabetic/severe combined immune-deficient repopulating cells using high-titer vesicular stomatitis virus G protein pseudotyped retrovirus. Blood. 1999 Apr 01; 93(7):2217-24. View Abstract
  40. Phase I/II trial of PIXY321 (granulocyte-macrophage colony stimulating factor/interleukin-3 fusion protein) for treatment of inherited and acquired marrow failure syndromes. Br J Haematol. 1998 Nov; 103(2):304-7. View Abstract
  41. Subtyping analysis of Fanconi anemia by immunoblotting and retroviral gene transfer. Mol Med. 1998 Jul; 4(7):468-79. View Abstract
  42. Identification of distinct elements of the stromal microenvironment that control human hematopoietic stem/progenitor cell growth and differentiation. Exp Hematol. 1998 Feb; 26(2):143-57. View Abstract
  43. Dye efflux studies suggest that hematopoietic stem cells expressing low or undetectable levels of CD34 antigen exist in multiple species. Nat Med. 1997 Dec; 3(12):1337-45. View Abstract
  44. Diamond-Blackfan anemia. Hematol Oncol Clin North Am. 1997 Dec; 11(6):1061-77. View Abstract
  45. The beta chain of the interleukin-3 receptor functionally associates with the erythropoietin receptor. Blood. 1997 Sep 01; 90(5):1867-73. View Abstract
  46. Preapheresis peripheral blood CD34+ mononuclear cell counts as predictors of progenitor cell yield. Transfusion. 1997 Jan; 37(1):79-85. View Abstract
  47. Selective transgene expression for detection and elimination of contaminating carcinoma cells in hematopoietic stem cell sources. J Clin Invest. 1996 Dec 01; 98(11):2539-48. View Abstract
  48. The beta c component of the granulocyte-macrophage colony-stimulating factor (GM-CSF)/interleukin 3 (IL-3)/IL-5 receptor interacts with a hybrid GM-CSF/erythropoietin receptor to influence proliferation and beta-globin mRNA expression. Mol Med. 1996 Nov; 2(6):766-73. View Abstract
  49. A constitutively activated chimeric cytokine receptor confers factor-independent growth in hematopoietic cell lines. Blood. 1996 Jul 15; 88(2):455-64. View Abstract
  50. Complete blockade of B7 family-mediated costimulation is necessary to induce human alloantigen-specific anergy: a method to ameliorate graft-versus-host disease and extend the donor pool. Blood. 1996 Jun 01; 87(11):4887-93. View Abstract
  51. Evidence for a physical association between the Shc-PTB domain and the beta c chain of the granulocyte-macrophage colony-stimulating factor receptor. J Biol Chem. 1996 May 24; 271(21):12137-40. View Abstract
  52. The collection and evaluation of peripheral blood progenitor cells sufficient for repetitive cycles of high-dose chemotherapy support. Transfusion. 1995 Oct; 35(10):837-44. View Abstract
  53. Ligand-dependent repression of the erythroid transcription factor GATA-1 by the estrogen receptor. Mol Cell Biol. 1995 Jun; 15(6):3147-53. View Abstract
  54. Clonality in juvenile chronic myelogenous leukemia. Blood. 1995 Jan 01; 85(1):21-30. View Abstract
  55. Expression and function of the human granulocyte-macrophage colony-stimulating factor receptor alpha subunit. Blood. 1994 Dec 15; 84(12):4174-85. View Abstract
  56. Hematopoietic cell proliferation and differentiation. Curr Opin Hematol. 1994 Jul; 1(4):310-20. View Abstract
  57. Synergistic effects of interleukin-11 with other growth factors on the expansion of murine hematopoietic progenitors and maintenance of stem cells in liquid culture. Exp Hematol. 1994 Apr; 22(4):353-9. View Abstract
  58. [Regulation of hematopoiesis]. Gematol Transfuziol. 1994 Mar-Apr; 39(2):3-10. View Abstract
  59. Human granulocyte-macrophage colony-stimulating factor receptor signal transduction requires the proximal cytoplasmic domains of the alpha and beta subunits. Blood. 1993 Dec 01; 82(11):3298-306. View Abstract
  60. In vitro enhancement of erythropoiesis by steel factor in Diamond-Blackfan anemia and treatment of other congenital cytopenias with recombinant interleukin 3/granulocyte-macrophage colony stimulating factor. Stem Cells. 1993 Jul; 11 Suppl 2:113-22. View Abstract
  61. A low-affinity human granulocyte-macrophage colony-stimulating factor/murine erythropoietin hybrid receptor functions in murine cell lines. Blood. 1993 Feb 01; 81(3):587-91. View Abstract
  62. The production of steel factor mRNA in Diamond-Blackfan anaemia long-term cultures and interactions of steel factor with erythropoietin and interleukin-3. Br J Haematol. 1992 Dec; 82(4):640-7. View Abstract
  63. Selective depletion of bone marrow T lymphocytes with anti-CD5 monoclonal antibodies: effective prophylaxis for graft-versus-host disease in patients with hematologic malignancies. Blood. 1991 Oct 15; 78(8):2139-49. View Abstract
  64. Inhibition of interleukin-1 by an interleukin-1 receptor antagonist prevents graft-versus-host disease. Blood. 1991 Oct 15; 78(8):1915-8. View Abstract
  65. New hats for hematopoietic hormones. Exp Hematol. 1991 Oct; 19(9):857-60. View Abstract
  66. A functional isoform of the human granulocyte/macrophage colony-stimulating factor receptor has an unusual cytoplasmic domain. Proc Natl Acad Sci U S A. 1991 Sep 01; 88(17):7744-8. View Abstract
  67. Restoration of phagocyte function by interferon-gamma in X-linked chronic granulomatous disease occurs at the level of a progenitor cell. Blood. 1990 Dec 15; 76(12):2443-8. View Abstract
  68. A phase I/II trial of recombinant granulocyte-macrophage colony-stimulating factor for children with aplastic anemia. Blood. 1990 Sep 15; 76(6):1077-82. View Abstract
  69. Biology and clinical aspects of the hematopoietic growth factors. Annu Rev Med. 1990; 41:483-96. View Abstract
  70. Hematopoiesis in vitro coexists with natural killer lymphocytes. Blood. 1989 Nov 15; 74(7):2376-82. View Abstract
  71. Granulocyte-macrophage colony-stimulating factor and interleukin-3 mRNAs are produced by a small fraction of blood mononuclear cells. Blood. 1989 Oct; 74(5):1525-30. View Abstract
  72. Expression of human interleukin-3 (multi-CSF) is restricted to human lymphocytes and T-cell tumor lines. Blood. 1989 Mar; 73(4):945-51. View Abstract
  73. Combinations of recombinant colony-stimulating factors are required for optimal hematopoietic differentiation in serum-deprived culture. Blood. 1989 Feb 15; 73(3):688-93. View Abstract
  74. Interleukin-1, tumor necrosis factor, and the production of colony-stimulating factors by cultured mesenchymal cells. Blood. 1988 Oct; 72(4):1316-23. View Abstract
  75. The biology of the colony stimulating factors. Behring Inst Mitt. 1988 Aug; (83):93-7. View Abstract
  76. Human colony-stimulating factors and stromal cell function. Soc Gen Physiol Ser. 1988; 43:47-55. View Abstract
  77. Combinations of purified recombinant colony-stimulating factors are required for optimal hematopoietic differentiation. Trans Assoc Am Physicians. 1988; 101:282-7. View Abstract
  78. The sources and actions of the human colony stimulating factors. Mead Johnson Symp Perinat Dev Med. 1988; (32):21-7. View Abstract
  79. Decreased hematopoietic accessory cell function following bone marrow transplantation. Exp Hematol. 1987 Nov; 15(10):1013-21. View Abstract
  80. Stimulation of human hematopoietic colony formation by recombinant gibbon multi-colony-stimulating factor or interleukin 3. J Clin Invest. 1987 Sep; 80(3):818-23. View Abstract
  81. Differential binding of erythroid and myeloid progenitors to fibroblasts and fibronectin. Blood. 1987 Jun; 69(6):1587-94. View Abstract
  82. Hematopoietic growth factors. J Clin Invest. 1987 Jun; 79(6):1549-57. View Abstract
  83. Gamma-interferon alters globin gene expression in neonatal and adult erythroid cells. Blood. 1987 Jun; 69(6):1674-81. View Abstract
  84. The production of hematopoietic growth factors by endothelial accessory cells. Blood Cells. 1987; 13(1-2):65-74. View Abstract
  85. The role of endothelial cells in hematopoiesis. Prog Clin Biol Res. 1987; 251:13-21. View Abstract
  86. The biological activities and uses of recombinant granulocyte-macrophage and multi-colony stimulating factors. Prog Hematol. 1987; 15:1-18. View Abstract
  87. Interleukin 1 induces cultured human endothelial cell production of granulocyte-macrophage colony-stimulating factor. J Clin Invest. 1987 Jan; 79(1):48-51. View Abstract
  88. Human recombinant granulocyte-macrophage colony-stimulating factor increases cell-to-cell adhesion and surface expression of adhesion-promoting surface glycoproteins on mature granulocytes. J Clin Invest. 1986 Aug; 78(2):597-601. View Abstract
  89. Stromal cell-associated erythropoiesis. Blood. 1986 May; 67(5):1418-26. View Abstract
  90. Isolation of a human stromal cell strain secreting hemopoietic growth factors. J Cell Physiol. 1986 Apr; 127(1):137-45. View Abstract
  91. Successful haploidentical mismatched bone marrow transplantation in severe combined immunodeficiency: T cell removal using CAMPATH-I monoclonal antibody and E-rosetting. Br J Haematol. 1986 Mar; 62(3):421-30. View Abstract
  92. Dependence of highly enriched human bone marrow progenitors on hemopoietic growth factors and their response to recombinant erythropoietin. J Clin Invest. 1986 Jan; 77(1):74-81. View Abstract
  93. Membrane antigen expression during hemopoietic differentiation. Crit Rev Oncol Hematol. 1986; 5(1):1-36. View Abstract
  94. Human recombinant granulocyte-macrophage colony-stimulating factor: a multilineage hematopoietin. Science. 1985 Dec 06; 230(4730):1171-3. View Abstract
  95. Purification of fetal hematopoietic progenitors and demonstration of recombinant multipotential colony-stimulating activity. J Clin Invest. 1985 Sep; 76(3):1286-90. View Abstract
  96. Selective expression of cell surface antigens on human haemopoietic progenitor cells. Prog Clin Biol Res. 1985; 184:301-15. View Abstract
  97. Pure red cell aplasia. Br J Haematol. 1983 Jul; 54(3):331-6. View Abstract
  98. Monoclonal antiglycophorin as a probe for erythroleukemias. Blood. 1983 Apr; 61(4):645-51. View Abstract
  99. Allogeneic bone-marrow transplantation in infantile malignant osteopetrosis. Lancet. 1983 Feb 26; 1(8322):437-41. View Abstract
  100. Antigen expression on normal and leukaemic erythroid precursors. Haematol Blood Transfus. 1983; 28:397-402. View Abstract
  101. Acute myeloid leukaemia in childhood: treatment in the United Kingdom. Haematol Blood Transfus. 1983; 28:51-5. View Abstract
  102. Changes in cell surface antigen expression during hemopoietic differentiation. Blood. 1982 Sep; 60(3):703-13. View Abstract
  103. Cellular immune defects to Epstein-Barr virus-determined antigens in young males. Cancer Res. 1981 Nov; 41(11 Pt 1):4284-91. View Abstract
  104. Documentation of Epstein-Barr virus infection in immunodeficient patients with life-threatening lymphoproliferative diseases by clinical, virological, and immunopathological studies. Cancer Res. 1981 Nov; 41(11 Pt 1):4226-36. View Abstract
  105. Monosomy 7 in childhood: a myeloproliferative disorder. Br J Haematol. 1981 Oct; 49(2):235-49. View Abstract
  106. Comparative antigenic phenotypes of normal and leukemic hemopoietic precursor cells analysed with a "library" of monoclonal antibodies. Haematol Blood Transfus. 1981; 26:296-304. View Abstract
  107. Acquired pure red-cell aplasia associated with an increase of T cells bearing receptors for the Fc of IgG. Acta Haematol. 1981; 65(4):270-4. View Abstract
  108. Expression of cell-surface HLA-DR, HLA-ABC and glycophorin during erythroid differentiation. Nature. 1981 Jan 01; 289(5793):68-71. View Abstract
  109. Mapping cell surface antigen expression of haemopoietic progenitor cells using monoclonal antibodies. Ciba Found Symp. 1981; 84:109-29. View Abstract
  110. Familial myelofibrosis. Arch Dis Child. 1980 Nov; 55(11):888-93. View Abstract
  111. The response of a child with primary sideroblastic anemia to cyclophosphamide. Blood. 1980 Aug; 56(2):323. View Abstract
  112. In vitro tests for distinguishing possible immune-mediated aplastic anemia from transfusion-induced sensitization. Blood. 1980 Feb; 55(2):211-5. View Abstract

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