DEVELOPMENTAL BIOLOGY OF HUMAN ERYTHROPOIESIS

Summary

Principal Investigator: Stuart H Orkin
Abstract: In this competitive renewal application of this Program Project grant now in its 30th year, multicjisciplinary approaches are employed to address the central theme of gene regulation in developing red blood cells. The premise underlying this work is that progress in the fundamental biology ofthe erythroid cell will provide critical, new knowledge that will have a positive impact on the management ofthe major red cell disorders, ncluding the hemoglobin disorders (sickle cell anemia and p-thalassemia), as well as congenital and acquired anemias. The Program utilizes multiple vertebrate systems (mouse, zebrafish, and human), contemporary genetics and cell biology, and emerging high-throughput chemical and shRNA screening procedures. Extensive interaction between the Project Leaders ensures intellectual vitality and synergy in execution of the proposed studies. The current proposals rest on exciting recent advances by the Project Leaders. In Project 1 (H. Lodish, Project Leader) new transcription factors, RNA polymerase II elongation factors, and chromatin-modifying enzymes important for terminal red cell development will be characterized. In Project 2 (S. Orkin, Project Leader) strategies will be developed to translate recent break-though findings in the study of fetal hemoglobin switching in humans to effective platforms for the discovery of new pathways or drugs suitable for directed reactivation of HbF in adult with hemoglobin disorders. In Project 3 (L. Zon, Project Leader) a newly discovered aspect of erythroid cell gene expression, transcriptional elongation, will be explored further in both the mouse and zebrafish through the study of conditional mutant mice and the role ofthe HEXIM complex in erythroid development. In Project 4 (A. Cantor, Project Leader) molecular approaches will be utilized to delineate the determinants that distinguish gene activation versus repression for the master erythroid factor GATA-1 during erythroid cell maturation. In Project 5 (B. Paw, Project Leader) new components ofthe complexes required for proper iron and heme trafficking in developing red cells will be characterized in both the zebrafish and mouse. Each ofthe Projects in this Program Project grant addresses important aspects of the expression program and function of erythroid cells Findings from these studies will provide new opportunities for the design of novel approaches to the management of red blood cell disorders.
Funding Period: 1997-07-01 - 2016-06-30
more information: NIH RePORT

Top Publications

  1. pmc Molecular cloning and functional characterization of zebrafish Slc4a3/Ae3 anion exchanger
    Boris E Shmukler
    Renal Division and Molecular and Vascular Medicine Division, Beth Israel Deaconess Medical Center Department of Medicine, Harvard Medical School, 99 Brookline Ave RN 380 F, Boston, MA, 02215, USA
    Pflugers Arch 466:1605-18. 2014
  2. pmc Formation of a PKCζ/β-catenin complex in endothelial cells promotes angiopoietin-1-induced collective directional migration and angiogenic sprouting
    Malika Oubaha
    Laboratory of Endothelial Cell Biology, Institut de Recherches Cliniques de Montreal, Universite de Montreal, QC, Canada
    Blood 120:3371-81. 2012
  3. pmc Cyclin D3 coordinates the cell cycle during differentiation to regulate erythrocyte size and number
    Vijay G Sankaran
    Broad Institute, Cambridge, Massachusetts 02142, USA
    Genes Dev 26:2075-87. 2012
  4. pmc Critical function for the Ras-GTPase activating protein RASA3 in vertebrate erythropoiesis and megakaryopoiesis
    Lionel Blanc
    Mammalian Genetics, New York Blood Center, New York, NY 10065, USA mail
    Proc Natl Acad Sci U S A 109:12099-104. 2012
  5. pmc Mutation mapping and identification by whole-genome sequencing
    Ignaty Leshchiner
    Genetics Division, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Genome Res 22:1541-8. 2012
  6. pmc Zebrafish globin switching occurs in two developmental stages and is controlled by the LCR
    Jared J Ganis
    Stem Cell Program and Division of Hematology Oncology, Children s Hospital and Dana Farber Cancer Institute, and Harvard Stem Cell Institute, Harvard Medical School, 1 Blackfan Cir, Karp 7, Boston, MA 02115, USA
    Dev Biol 366:185-94. 2012
  7. pmc Heme metabolism and erythropoiesis
    Jacky Chung
    Division of Hematology, Brigham and Women s Hospital, Boston, Massachusetts, USA
    Curr Opin Hematol 19:156-62. 2012
  8. pmc Mammalian erythroblast enucleation requires PI3K-dependent cell polarization
    Junxia Wang
    Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, 117604 Singapore
    J Cell Sci 125:340-9. 2012
  9. pmc Cellular and mitochondrial iron homeostasis in vertebrates
    Caiyong Chen
    Department of Medicine, Hematology Division, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Biochim Biophys Acta 1823:1459-67. 2012
  10. pmc ABCB6 mutations cause ocular coloboma
    Lejin Wang
    Department of Ophthalmology, Peking University Third Hospital, Beijing, China
    Am J Hum Genet 90:40-8. 2012

Research Grants

  1. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
  2. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
  3. Endothelial Cell Phenotypes in Health and Disease
    William C Aird; Fiscal Year: 2013
  4. Immune Responses To AAV-Mediated FIX Gene Transfer
    Hildegund C J Ertl; Fiscal Year: 2013
  5. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
  6. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
  7. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
  8. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
  9. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
  10. Chemistry and Biology of Coagulation
    Sriram Krishnaswamy; Fiscal Year: 2013

Detail Information

Publications79

  1. pmc Molecular cloning and functional characterization of zebrafish Slc4a3/Ae3 anion exchanger
    Boris E Shmukler
    Renal Division and Molecular and Vascular Medicine Division, Beth Israel Deaconess Medical Center Department of Medicine, Harvard Medical School, 99 Brookline Ave RN 380 F, Boston, MA, 02215, USA
    Pflugers Arch 466:1605-18. 2014
    ..We conclude that multiple repeat elements have disrupted the 5'-end of the zebrafish ae3 gene, associated with N-terminal truncation of the protein and reduced anion transport activity...
  2. pmc Formation of a PKCζ/β-catenin complex in endothelial cells promotes angiopoietin-1-induced collective directional migration and angiogenic sprouting
    Malika Oubaha
    Laboratory of Endothelial Cell Biology, Institut de Recherches Cliniques de Montreal, Universite de Montreal, QC, Canada
    Blood 120:3371-81. 2012
    ..These results reveal that PKCζ and β-catenin function in a complex at adherens junctions and at the leading edge of migrating endothelial cells to modulate collective and directional migration during angiogenesis...
  3. pmc Cyclin D3 coordinates the cell cycle during differentiation to regulate erythrocyte size and number
    Vijay G Sankaran
    Broad Institute, Cambridge, Massachusetts 02142, USA
    Genes Dev 26:2075-87. 2012
    ..We illustrate how cell type-specific specialization can occur for general cell cycle components-a finding resulting from the biological follow-up of unbiased human genetic studies...
  4. pmc Critical function for the Ras-GTPase activating protein RASA3 in vertebrate erythropoiesis and megakaryopoiesis
    Lionel Blanc
    Mammalian Genetics, New York Blood Center, New York, NY 10065, USA mail
    Proc Natl Acad Sci U S A 109:12099-104. 2012
    ..Notably, the scat phenotype is recapitulated in zebrafish when rasa3 is silenced. These results highlight a critical, conserved, and nonredundant role for RASA3 in vertebrate hematopoiesis...
  5. pmc Mutation mapping and identification by whole-genome sequencing
    Ignaty Leshchiner
    Genetics Division, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Genome Res 22:1541-8. 2012
    ..Our novel methodology and online tools will make next-generation sequencing an easily applicable resource for mutation mapping in all model systems...
  6. pmc Zebrafish globin switching occurs in two developmental stages and is controlled by the LCR
    Jared J Ganis
    Stem Cell Program and Division of Hematology Oncology, Children s Hospital and Dana Farber Cancer Institute, and Harvard Stem Cell Institute, Harvard Medical School, 1 Blackfan Cir, Karp 7, Boston, MA 02115, USA
    Dev Biol 366:185-94. 2012
    ..Our studies provide a comprehensive characterization of the zebrafish globin loci and clarify the regulation of globin switching...
  7. pmc Heme metabolism and erythropoiesis
    Jacky Chung
    Division of Hematology, Brigham and Women s Hospital, Boston, Massachusetts, USA
    Curr Opin Hematol 19:156-62. 2012
    ..Heme can also be acquired by intestinal absorption and intercellular transport. The purpose of this review is to highlight recent work on heme and iron transport with an emphasis on their relevance in erythropoiesis...
  8. pmc Mammalian erythroblast enucleation requires PI3K-dependent cell polarization
    Junxia Wang
    Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, 117604 Singapore
    J Cell Sci 125:340-9. 2012
    ..We propose that enucleation is regulated by microtubules and PI3K signaling in a manner mechanistically similar to directed cell locomotion...
  9. pmc Cellular and mitochondrial iron homeostasis in vertebrates
    Caiyong Chen
    Department of Medicine, Hematology Division, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Biochim Biophys Acta 1823:1459-67. 2012
    ..This article is part of a Special Issue entitled: Cell Biology of Metals...
  10. pmc ABCB6 mutations cause ocular coloboma
    Lejin Wang
    Department of Ophthalmology, Peking University Third Hospital, Beijing, China
    Am J Hum Genet 90:40-8. 2012
    ..Our results demonstrate that ABCB6 mutations cause ocular coloboma...
  11. pmc Lineage regulators direct BMP and Wnt pathways to cell-specific programs during differentiation and regeneration
    Eirini Trompouki
    Stem Cell Program and Division of Hematology Oncology, Children s Hospital Boston, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA
    Cell 147:577-89. 2011
    ..We conclude that the regenerative response mediated by BMP and Wnt signaling pathways is coupled with the lineage master regulators to control the gene programs defining cellular identity...
  12. pmc From stem cell to red cell: regulation of erythropoiesis at multiple levels by multiple proteins, RNAs, and chromatin modifications
    Shilpa M Hattangadi
    Whitehead Institute for Biomedical Research, Cambridge, MA, USA
    Blood 118:6258-68. 2011
    ..We discuss the complex intracellular networks of coordinated gene regulation by transcription factors, chromatin modifiers, and miRNAs that regulate the different stages of erythropoiesis...
  13. ncbi Chromatin immunoprecipitation in adult zebrafish red cells
    Eirini Trompouki
    Stem Cell Program, Children s Hospital Boston, Harvard Stem Cell Institute, Harvard Medical School and Howard Hughes Medical Institute, Boston, Massachusetts, USA
    Methods Cell Biol 104:341-52. 2011
    ..This technique has been used extensively and successfully in other systems and it will be a useful tool for studying epigenetics in zebrafish...
  14. ncbi Genetic suppressor screens in haploids
    Xiaoying Bai
    Howard Hughes Medical Institute, Boston, Massachusetts, USA
    Methods Cell Biol 104:129-36. 2011
    ..This strategy will greatly broaden the utility of the zebrafish as a model for making original discoveries and establishing novel paradigms for understanding vertebrate biology...
  15. pmc Role of ZBP-89 in human globin gene regulation and erythroid differentiation
    Andrew J Woo
    Division of Pediatric Hematology Oncology, Children s Hospital Boston and Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
    Blood 118:3684-93. 2011
    ..Addition of the histone deacetylase inhibitor valproic acid partially reverses the reduced globin gene expression. These findings reveal an activating role for ZBP-89 in human globin gene regulation and erythroid differentiation...
  16. pmc Abnormal mitoferrin-1 expression in patients with erythropoietic protoporphyria
    Yongming Wang
    Department of Medicine and Liver Center, University of Alabama at Birmingham, Birmingham, Alabama 35294 0005, USA
    Exp Hematol 39:784-94. 2011
    ..The major focus was mitoferrin-1 (MFRN1), the mitochondrial transporter of Fe used for heme formation by FECH and for 2Fe2S cluster synthesis, which is critical to FECH activity/stability...
  17. pmc Formation of mammalian erythrocytes: chromatin condensation and enucleation
    Peng Ji
    Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA
    Trends Cell Biol 21:409-15. 2011
    ..In this review, we discuss recent advances in mammalian erythroblast chromatin condensation and enucleation, and conclude with our perspectives on future studies...
  18. pmc Targeted deletion of the mouse Mitoferrin1 gene: from anemia to protoporphyria
    Marie Berengere Troadec
    Department of Pathology, School of Medicine, University of Utah, 50 North Medical Drive, Salt Lake City, UT 84132, USA
    Blood 117:5494-502. 2011
    ..Our results show that the activity of mitoferrin1 is required to manage an increase in heme synthesis. The data also show that alterations in heme synthesis within hepatocytes can lead to protoporphyria and hepatotoxicity...
  19. pmc Teleost growth factor independence (gfi) genes differentially regulate successive waves of hematopoiesis
    Jeffrey D Cooney
    Department of Medicine, Division of Hematology, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Dev Biol 373:431-41. 2013
    ..Our studies establish a comparative paradigm for the regulation of hematopoietic lineages by gfi transcription factors...
  20. pmc Regulation of mammalian cell differentiation by long non-coding RNAs
    Wenqian Hu
    Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
    EMBO Rep 13:971-83. 2012
    ..We focus on several representative differentiation systems and discuss how specific long non-coding RNAs contribute to the regulation of mammalian development...
  21. pmc Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts
    Dhvanit I Shah
    Department of Medicine, Division of Hematology, Brigham and Women s Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA
    Nature 491:608-12. 2012
    ..An ATPIF1 deficiency may contribute to important human diseases, such as congenital sideroblastic anaemias and mitochondriopathies...
  22. pmc Long noncoding RNAs during normal and malignant hematopoiesis
    Juan R Alvarez-Dominguez
    Whitehead Institute for Biomedical Research, Cambridge, MA, 02142, USA
    Int J Hematol 99:531-41. 2014
    ..Thus, lncRNAs may be not only useful as markers for the diagnosis and prognosis of cancers of the blood, but also as potential targets for novel therapies. ..
  23. pmc Global analysis of induced transcription factors and cofactors identifies Tfdp2 as an essential coregulator during terminal erythropoiesis
    Cynthia Chen
    Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, Cambridge, MA, USA Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
    Exp Hematol 42:464-76.e5. 2014
    ....
  24. pmc Transcriptional divergence and conservation of human and mouse erythropoiesis
    Novalia Pishesha
    Whitehead Institute for Biomedical Research, Cambridge, MA 02142
    Proc Natl Acad Sci U S A 111:4103-8. 2014
    ....
  25. pmc Iron regulatory protein-1 protects against mitoferrin-1-deficient porphyria
    Jacky Chung
    From the Division of Hematology, Brigham and Women s Hospital Division of Hematology Oncology, Boston Children s Hospital and Harvard Medical School, Boston, Massachusetts 02115
    J Biol Chem 289:7835-43. 2014
    ..Together, our data support a model whereby impaired mitochondrial [Fe-S] cluster biogenesis in Mfrn1(gt/gt) cells results in elevated IRP1 RNA-binding that attenuates ALAS2 mRNA translation and protoporphyrin accumulation...
  26. ncbi A Cdx4-Sall4 regulatory module controls the transition from mesoderm formation to embryonic hematopoiesis
    Elizabeth J Paik
    Stem Cell Program and Division of Hematology Oncology, Boston Children s Hospital, Harvard Stem Cell Institute, Harvard Medical School and Howard Hughes Medical Institute, Boston, MA 02115, USA
    Stem Cell Reports 1:425-36. 2013
    ..These findings suggest that auto- and cross-regulation of Cdx4 and Sall4 establish a stable molecular circuit in the mesoderm that facilitates the activation of the blood-specific program as development proceeds. ..
  27. pmc Global discovery of erythroid long noncoding RNAs reveals novel regulators of red cell maturation
    Juan R Alvarez-Dominguez
    Whitehead Institute for Biomedical Research, Cambridge, MA
    Blood 123:570-81. 2014
    ..Our study provides an annotated catalog of erythroid lncRNAs, readily available through an online resource, and shows that diverse types of lncRNAs participate in the regulatory circuitry underlying erythropoiesis. ..
  28. pmc Macrocytic anemia and mitochondriopathy resulting from a defect in sideroflexin 4
    Gordon J Hildick-Smith
    Division of Hematology, Department of Medicine, Brigham and Women s Hospital and Harvard Medical School, Boston, MA 02115, USA
    Am J Hum Genet 93:906-14. 2013
    ..Our findings establish mutations in SFXN4 as a cause of mitochondriopathy and macrocytic anemia. ..
  29. pmc An erythroid enhancer of BCL11A subject to genetic variation determines fetal hemoglobin level
    Daniel E Bauer
    Division of Hematology Oncology, Boston Children s Hospital, Boston, MA 02115, USA
    Science 342:253-7. 2013
    ..We propose the GWAS-marked BCL11A enhancer represents an attractive target for therapeutic genome engineering for the β-hemoglobinopathies. ..
  30. pmc Cloning expeditions: risky but rewarding
    Harvey Lodish
    Whitehead Institute for Biomedical Research, Departments of Biology and Biological Engineering, MIT, Cambridge, Massachusetts, USA
    Mol Cell Biol 33:4620-7. 2013
    ..Unsurprisingly, all have gone on to become leaders in the fields of molecular cell biology and molecular medicine. ..
  31. pmc Distinct neuroblastoma-associated alterations of PHOX2B impair sympathetic neuronal differentiation in zebrafish models
    Desheng Pei
    Department of Pediatric Oncology, Dana Farber Cancer Institute, Division of Hematology Oncology, Boston Children s Hospital, Harvard Medical School, Boston, MA, USA
    PLoS Genet 9:e1003533. 2013
    ....
  32. pmc ZFP36L2 is required for self-renewal of early burst-forming unit erythroid progenitors
    Lingbo Zhang
    Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02142, USA
    Nature 499:92-6. 2013
    ..ZFP36L2 therefore functions as part of a molecular switch promoting BFU-E self-renewal and a subsequent increase in the total numbers of colony-forming unit-erythroid (CFU-E) progenitors and erythroid cells that are generated. ..
  33. pmc Site-directed zebrafish transgenesis into single landing sites with the phiC31 integrase system
    Christian Mosimann
    Howard Hughes Medical Institute, Boston, MA 02115, USA
    Dev Dyn 242:949-63. 2013
    ..The phiC31 integrase catalyzes the unidirectional recombination reaction between heterotypic attP and attB sites and is an efficient platform for site-directed transgenesis...
  34. pmc ATP-binding cassette B10 regulates early steps of heme synthesis
    Marina Bayeva
    Feinberg Cardiovascular Research Institute, Northwestern University School of Medicine, Chicago, IL, USA
    Circ Res 113:279-87. 2013
    ....
  35. ncbi Genome-wide association studies of hematologic phenotypes: a window into human hematopoiesis
    Vijay G Sankaran
    Division of Hematology Oncology, Boston Children s Hospital and Department of Pediatric Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, United States
    Curr Opin Genet Dev 23:339-44. 2013
    ..We discuss how the resulting insight from these studies promises to increase our understanding of human hematopoiesis and outline the challenges that lay ahead in this field. ..
  36. pmc Snx3 regulates recycling of the transferrin receptor and iron assimilation
    Caiyong Chen
    Department of Medicine, Division of Hematology, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA
    Cell Metab 17:343-52. 2013
    ..Our findings uncover a role of Snx3 in regulating Tfrc recycling, iron homeostasis, and erythropoiesis. Thus, the identification of Snx3 provides a genetic tool for exploring erythropoiesis and disorders of iron metabolism...
  37. pmc Fetal hepatic progenitors support long-term expansion of hematopoietic stem cells
    Song Chou
    Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
    Exp Hematol 41:479-490.e4. 2013
    ..In contrast, DLK(-) cells are incapable of expanding hematopoietic cells, demonstrating that hepatic progenitors are the principle supportive cells for HSC expansion in the fetal liver...
  38. pmc TiF1-gamma plays an essential role in murine hematopoiesis and regulates transcriptional elongation of erythroid genes
    Xiaoying Bai
    Stem Cell Program, Children s Hospital Boston, Boston, MA 02115, USA
    Dev Biol 373:422-30. 2013
    ..Our study therefore demonstrates that TIF1γ plays essential roles in multiple murine blood lineages and that its function in transcription elongation is evolutionally conserved...
  39. pmc Identification of distal cis-regulatory elements at mouse mitoferrin loci using zebrafish transgenesis
    Julio D Amigo
    Department of Medicine, Division of Hematology, Brigham and Women s Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA
    Mol Cell Biol 31:1344-56. 2011
    ....
  40. pmc MicroRNA-15a and -16-1 act via MYB to elevate fetal hemoglobin expression in human trisomy 13
    Vijay G Sankaran
    Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
    Proc Natl Acad Sci U S A 108:1519-24. 2011
    ....
  41. pmc HIF1alpha synergizes with glucocorticoids to promote BFU-E progenitor self-renewal
    Johan Flygare
    Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
    Blood 117:3435-44. 2011
    ....
  42. pmc Oncogenic Kras-induced leukemogeneis: hematopoietic stem cells as the initial target and lineage-specific progenitors as the potential targets for final leukemic transformation
    Jing Zhang
    Whitehead Institute for Biomedical Research, Cambridge, MA, USA
    Blood 113:1304-14. 2009
    ..Our model might be also applicable to other solid tumors harboring oncogenic Kras mutations...
  43. ncbi Human fetal hemoglobin expression is regulated by the developmental stage-specific repressor BCL11A
    Vijay G Sankaran
    Division of Hematology Oncology, Children s Hospital Boston, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA
    Science 322:1839-42. 2008
    ..BCL11A emerges as a therapeutic target for reactivation of HbF in beta-hemoglobin disorders...
  44. pmc Hematopoiesis: an evolving paradigm for stem cell biology
    Stuart H Orkin
    Division of Hematology Oncology, Children s Hospital Boston and the Dana Farber Cancer Institute, Harvard Stem Cell Institute, Harvard Medical School, Boston, MA 02115, USA
    Cell 132:631-44. 2008
    ....
  45. ncbi Enucleation of cultured mouse fetal erythroblasts requires Rac GTPases and mDia2
    Peng Ji
    Whitehead Institute for Biomedical Research, Department of Biology, Massachusetts Institute of Technology, 9 Cambridge Center, Floor 6, Cambridge, MA 02142, USA
    Nat Cell Biol 10:314-21. 2008
    ..These results reveal important roles for Rac GTPases and their effector mDia2 in enucleation of mammalian erythroblasts...
  46. ncbi Dimerization by a cytokine receptor is necessary for constitutive activation of JAK2V617F
    Xiaohui Lu
    Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
    J Biol Chem 283:5258-66. 2008
    ..The structure of the activated JAK2V617F is thus likely to be different from that of the activated wild-type JAK2, raising the possibility of developing a specifically targeted therapy for myeloproliferative disorders...
  47. ncbi Zebrafish ae2.2 encodes a second slc4a2 anion exchanger
    Boris E Shmukler
    Molecular and Vascular Medicine and Renal Units, Beth Israel Deaconess Medical Center E RW763, 330 Brookline Ave, Boston, MA 02215, USA
    Am J Physiol Regul Integr Comp Physiol 294:R1081-91. 2008
    ..1 mRNA, or of both with nontoxic or minimally toxic levels of N-morpholino oligomers produced no grossly detectable morphological phenotype, and preserved normal structure of the head and the pronephric duct at 24 h postfertilization...
  48. ncbi Endogenous K-ras signaling in erythroid differentiation
    Jing Zhang
    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts, USA
    Cell Cycle 6:1970-3. 2007
    ..These results support the notion that in human cancer patients oncogenic Ras signaling might be controlled by antagonizing essential cytokines...
  49. pmc Signals emanating from the membrane proximal region of the thrombopoietin receptor (mpl) support hematopoietic stem cell self-renewal
    Wei Tong
    Whitehead Institute for Biomedical Research, Nine Cambridge Center, Cambridge, Massachusetts, USA
    Exp Hematol 35:1447-55. 2007
    ..This deletion removes three major signaling tyrosines on the mpl cytoplasmic domain, but retains the membrane proximal Box1 and Box2 domains required for JAK2 activation...
  50. pmc Alpha4beta1 integrin and erythropoietin mediate temporally distinct steps in erythropoiesis: integrins in red cell development
    Shawdee Eshghi
    Division of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    J Cell Biol 177:871-80. 2007
    ....
  51. pmc Expression of oncogenic K-ras from its endogenous promoter leads to a partial block of erythroid differentiation and hyperactivation of cytokine-dependent signaling pathways
    Jing Zhang
    Whitehead Institute for Biomedical Research, Cambridge, MA, USA
    Blood 109:5238-41. 2007
    ..Our results support efforts to modulate Ras signaling for treating hematopoietic malignancies...
  52. pmc JAK2 exon 12 mutations in polycythemia vera and idiopathic erythrocytosis
    Linda M Scott
    University of Cambridge, Cambridge, United Kingdom
    N Engl J Med 356:459-68. 2007
    ..However, the molecular basis of these myeloproliferative disorders in patients without the V617F mutation is unclear...
  53. ncbi The membrane-proximal region of the thrombopoietin receptor confers its high surface expression by JAK2-dependent and -independent mechanisms
    Wei Tong
    Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
    J Biol Chem 281:38930-40. 2006
    ..Our study suggests that whereas cell surface expression of type I cytokine receptors requires their cognate JAKs, the mechanisms governing receptor-JAK interactions differ among receptors interacting with the same JAK protein...
  54. ncbi A "classical" homodimeric erythropoietin receptor is essential for the antiapoptotic effects of erythropoietin on differentiated neuroblastoma SH-SY5Y and pheochromocytoma PC-12 cells
    Moonkyoung Um
    Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA
    Cell Signal 19:634-45. 2007
    ....
  55. ncbi Active conformation of the erythropoietin receptor: random and cysteine-scanning mutagenesis of the extracellular juxtamembrane and transmembrane domains
    Xiaohui Lu
    Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA
    J Biol Chem 281:7002-11. 2006
    ..Based on our data and the previously determined structure of Epo bound to a dimer of the EpoR extracellular domain, we present a model of the active and inactive conformations of the Epo receptor...
  56. ncbi Antiapoptotic effects of erythropoietin in differentiated neuroblastoma SH-SY5Y cells require activation of both the STAT5 and AKT signaling pathways
    Moonkyoung Um
    Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology, 9 Cambridge Center, Cambridge, MA 02142, USA
    J Biol Chem 281:5648-56. 2006
    ....
  57. ncbi Cellular trafficking and degradation of erythropoietin and novel erythropoiesis stimulating protein (NESP)
    Alec W Gross
    Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA
    J Biol Chem 281:2024-32. 2006
    ..Our kinetic model of Epo and NESP receptor binding, intracellular trafficking, and degradation explains why Epo is degraded faster than NESP at the cellular level...
  58. pmc AKT induces erythroid-cell maturation of JAK2-deficient fetal liver progenitor cells and is required for Epo regulation of erythroid-cell differentiation
    Saghi Ghaffari
    Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    Blood 107:1888-91. 2006
    ....
  59. pmc Regulation of mitochondrial iron import through differential turnover of mitoferrin 1 and mitoferrin 2
    Prasad N Paradkar
    Department of Pathology, University of Utah School of Medicine, Salt Lake City, Utah 84132, USA
    Mol Cell Biol 29:1007-16. 2009
    ..These results suggest that mitochondrial iron accumulation is tightly regulated and that controlling mitoferrin levels within the mitochondrial membrane provides a mechanism to regulate mitochondrial iron levels...
  60. pmc Symmetric signaling by an asymmetric 1 erythropoietin: 2 erythropoietin receptor complex
    Yingxin L Zhang
    Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
    Mol Cell 33:266-74. 2009
    ..We conclude that despite asymmetry in the ligand-receptor interaction, both sides are competent for signaling, and appear to signal equally...
  61. pmc Zebrafish kidney stromal cell lines support multilineage hematopoiesis
    David L Stachura
    Division of Biological Sciences, Section of Cell and Developmental Biology, University of California at San Diego, La Jolla, CA 92093 0380, USA
    Blood 114:279-89. 2009
    ..The development of robust in vitro assays now provide the means to track defined, functional outcomes for prospectively isolated blood cell subsets in the zebrafish...
  62. pmc Therapeutic levels of fetal hemoglobin in erythroid progeny of β-thalassemic CD34+ cells after lentiviral vector-mediated gene transfer
    Andrew Wilber
    Department of Surgery, Southern Illinois University School of Medicine, Springfield, IL, USA
    Blood 117:2817-26. 2011
    ..These observations suggest that both lentiviral-mediated γ-globin gene addition and genetic reactivation of endogenous γ-globin genes have potential to provide therapeutic HbF levels to patients with β-globin deficiency...
  63. pmc Ubiquitous transgene expression and Cre-based recombination driven by the ubiquitin promoter in zebrafish
    Christian Mosimann
    Howard Hughes Medical Institute, Boston, MA 02115, USA
    Development 138:169-77. 2011
    ..The ubi promoter and the transgenic lines presented here thus provide a broad resource and important advancement for transgenic applications in zebrafish...
  64. pmc Intoxication of zebrafish and mammalian cells by cholera toxin depends on the flotillin/reggie proteins but not Derlin-1 or -2
    David E Saslowsky
    Division of Gastroenterology, Children s Hospital, Boston, Massachusetts, USA
    J Clin Invest 120:4399-4409. 2010
    ..These results revise current models for CT intoxication and implicate protein scaffolding of lipid rafts in the endo-somal sorting of the toxin-GM1 complex...
  65. pmc Down-regulation of Myc is essential for terminal erythroid maturation
    Senthil Raja Jayapal
    Computation and Systems Biology, Singapore Massachusetts Institute of Technology Alliance, 4 Engineering Drive 3, Singapore
    J Biol Chem 285:40252-65. 2010
    ..These results reveal an important dose-dependent function of Myc in regulating terminal maturation in mammalian erythroid cells...
  66. pmc Histone deacetylase 2 is required for chromatin condensation and subsequent enucleation of cultured mouse fetal erythroblasts
    Peng Ji
    Whitehead Institute for Biomedical Research, Cambridge, 9 Cambridge Center, Cambridge, MA, USA
    Haematologica 95:2013-21. 2010
    ..However, it is not clear how chromatin condensation is achieved and whether it is required for enucleation...
  67. pmc miR-451 protects against erythroid oxidant stress by repressing 14-3-3zeta
    Duonan Yu
    Division of Hematology, The Children s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
    Genes Dev 24:1620-33. 2010
    ..Our findings define a novel miRNA-regulated pathway that protects erythrocytes against oxidant stress, and, more generally, illustrate how a miRNA can influence gene expression by altering the activity of a key transcription factor...
  68. pmc TIF1gamma controls erythroid cell fate by regulating transcription elongation
    Xiaoying Bai
    Howard Hughes Medical Institute, Boston, MA 02115, USA
    Cell 142:133-43. 2010
    ..Our study establishes a mechanism for regulating tissue cell fate and differentiation through transcription elongation...
  69. pmc Iron and porphyrin trafficking in heme biogenesis
    Iman J Schultz
    Department of Medicine, Hematology Division, Brigham and Women s Hospital, Children s Hospital Boston, Harvard Medical School, Boston, Massachusetts 02115, USA
    J Biol Chem 285:26753-9. 2010
    ....
  70. pmc Ferrochelatase forms an oligomeric complex with mitoferrin-1 and Abcb10 for erythroid heme biosynthesis
    Wen Chen
    Department of Medicine, Hematology Division, Brigham and Women s Hospital, 1 Blackfan Circle, Boston, MA 02115, USA
    Blood 116:628-30. 2010
    ..Our findings imply that Fech forms an oligomeric complex with Mfrn1 and Abcb10 to synergistically integrate mitochondrial iron importation and use for heme biosynthesis...
  71. pmc From stem cell to erythroblast: regulation of red cell production at multiple levels by multiple hormones
    Harvey Lodish
    Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
    IUBMB Life 62:492-6. 2010
    ....
  72. pmc Homeodomain-interacting protein kinase 2 plays an important role in normal terminal erythroid differentiation
    Shilpa M Hattangadi
    Whitehead Institute for Biomedical Research, Cambridge, MA 02142, USA
    Blood 115:4853-61. 2010
    ....
  73. pmc Pathogenesis of the erythroid failure in Diamond Blackfan anaemia
    Colin A Sieff
    Whitehead Institute for Biomedical Research, Cambridge, MA, USA
    Br J Haematol 148:611-22. 2010
    ....
  74. pmc Insights into GATA-1-mediated gene activation versus repression via genome-wide chromatin occupancy analysis
    Ming Yu
    Department of Pediatric Hematology Oncology, Children s Hospital Boston and Dana Farber Cancer Institute, Harvard Medical School, MA 02115, USA
    Mol Cell 36:682-95. 2009
    ..These data provide insights into GATA-1-mediated gene regulation in vivo...
  75. pmc Abcb10 physically interacts with mitoferrin-1 (Slc25a37) to enhance its stability and function in the erythroid mitochondria
    Wen Chen
    Department of Medicine, Hematology Division, Brigham and Women s Hospital, and Hematology Oncology Division, Children s Hospital Boston, Harvard Medical School, Boston, MA 02115, USA
    Proc Natl Acad Sci U S A 106:16263-8. 2009
    ....
  76. pmc Discovery of genes essential for heme biosynthesis through large-scale gene expression analysis
    Roland Nilsson
    Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
    Cell Metab 10:119-30. 2009
    ..Our results advance the molecular understanding of heme biosynthesis and offer promising candidate genes for inherited anemias...
  77. pmc Translational isoforms of FOG1 regulate GATA1-interacting complexes
    Jonathan W Snow
    Division of Hematology Oncology, Children s Hospital, Boston, Massachusetts 02115, USA
    J Biol Chem 284:29310-9. 2009
    ....
  78. pmc In vivo inactivation of MASTL kinase results in thrombocytopenia
    H Jan Johnson
    Puget Sound Blood Center, Seattle, Wash 98104 1256, USA
    Exp Hematol 37:901-8. 2009
    ..We wanted to determine the expression and localization of MASTL, as well as its role in developing thrombocytes using an in vivo model system...
  79. pmc Erythropoietin stimulates phosphorylation and activation of GATA-1 via the PI3-kinase/AKT signaling pathway
    Wei Zhao
    Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    Blood 107:907-15. 2006
    ..These data demonstrate that EpoR signaling phosphorylates GATA-1 and modulates its activity via the PI3-kinase/AKT signaling pathway...

Research Grants30

  1. HORMONAL REGULATION OF BLOOD PRESSURE
    Michal Laniado Schwartzman; Fiscal Year: 2013
    ..ular tone, in the pathophysiology of hypertension and cardiovascular disease. ..
  2. Neuro-Circulatory Function in Chronic Heart Failure
    Irving H Zucker; Fiscal Year: 2013
    ..The role of exercise training in modulating ROS generation and antioxidant enzymes in animals with CHF will also be investigated in this project. ..
  3. Endothelial Cell Phenotypes in Health and Disease
    William C Aird; Fiscal Year: 2013
    ..Core C ("Gene Targeting Core";William C. Aird, Core Leader) provides the necessary tools for targeting the Hprt locus and the loci of endogenous genes in ES cells and mice. ..
  4. Immune Responses To AAV-Mediated FIX Gene Transfer
    Hildegund C J Ertl; Fiscal Year: 2013
    ..HC ErtI): T Cells to AAV and AAV-Encoded Transgene Products Project 3 (RW Herzog, C Terliorst): Pathways Towards Immune Tolerance to Coagulation Factors Core A (HC ErtI): Administrative Core Core B (S Zliou): Vector Core ..
  5. Thrombus Formation and Antithrombotic Intervention
    John H Griffin; Fiscal Year: 2013
    ..New knowledge will contribute to improving prevention, diagnosis and treatment of relevant diseases related to thrombosis. ..
  6. Mechanisms of Atherogenesis in Insulin Resistance
    IRA A TABAS; Fiscal Year: 2013
    ..End of Abstract) ..
  7. Pacific NorthWest Regional Center of Excellence (PNWRCE)
    Jay A Nelson; Fiscal Year: 2013
    ..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
  8. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  9. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  10. Chemistry and Biology of Coagulation
    Sriram Krishnaswamy; Fiscal Year: 2013
    ..This program seeks to develop new information by which key reactions of blood clotting are regulated. This information will lead to new concepts and strategies for the treatment of blood clotting-related human disease. ..
  11. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..
  12. Semi-volatile PCBs: Sources, Exposures, Toxicities
    Larry W Robertson; Fiscal Year: 2013
    ..These data and dietary studies in the last Aim will provide a scientific basis for risk assessment and advice for stakeholders with the ultimate goal to protect highly-exposed individuals and populations. ..
  13. Rocky Mountain Regional Center of Excellence or Biodefense and Emerging Infectiou
    John T Belisle; Fiscal Year: 2013
    ..abstract_text> ..
  14. Cell Adhesion Mechanisms in Vascular Disease &Thrombosis
    MARK HOWARD GINSBERG; Fiscal Year: 2013
    ..abstract_text> ..
  15. UNMC EPPLEY CANCER CENTER SUPPORT GRANT
    Kenneth H Cowan; Fiscal Year: 2013
    ....