PRE- AND POSTGRADUATE TRAINING IN MOLECULAR HEMATOLOGY

Summary

Principal Investigator: J Evan Sadler
Abstract: DESCRIPTION (provided by applicant): Although advances in hematology have led the way in many fields of basic and translational biomedical research, hematologic diseases remain major threats to public health. For example, the prognosis for many hematologic malignancies continues to be poor. Current treatments are inadequate to support a normal lifestyle for most patients with for sickle cell disease. In the U.S., at least 500,000 venous thromboembolic events, 1.1 million heart attacks and 150,000 stroke deaths occur each year. At the same time, the opportunities for hematology research have never been more promising, and converting these opportunities into medical advances will depend upon training the next generation of basic and translational hematology researchers. The Molecular Hematology training program proposes to fill this need for 5 predoctoral and 8 postdoctoral trainees per year. Predoctoral Ph.D. and M.D./PhD students follow the curriculum of the Washington University graduate school. After passing their qualifying examination, they enter the laboratory of participating faculty Mentors (currently 23) for 3-4 years of laboratory research to complete their dissertation. Postdoctoral Ph.D. trainees from around the world apply to participating laboratories;postdoctoral M.D. and M.D./Ph.D. trainees usually have completed the clinical training component of a Hematology-Oncology fellowship program at Washington University or elsewhere. The duration of postdoctoral training depends on prior experience. Those with Ph.D. or M.D./PhD degrees typically conduct research for 2-3 years before transitioning to an independent research position, whereas those with an M.D. degree may benefit from 3-4 years of postdoctoral training. Trainees receive intensive mentoring and career counseling, and participate in coursework, journal clubs, and seminars. The major facilities of the program consist of 55,000 square feet of fully-equipped laboratory space that house the Divisions of Hematology and Oncology, as well as extensive institutional resources for genome sequencing, crystallography, computational biology, animal studies, and patient-oriented clinical research. The research topics available to trainees reflect the multidisciplinary expertise of the participating Mentors and include: pathogenesis of hemorrhagic and thrombotic disorders;regulation of blood coagulation and fibrinolysis;gene therapy of hemophilia and lysosomal storage diseases;phosphoinositide metabolism and cell signaling pathways;mechanisms of hematopoiesis;telomerase and ribosomal protein defects in bone marrow failure syndromes;molecular basis for protein trafficking in mammalian cells;role of platelets and angiogenesis in metastasis;biology of human immunodeficiency and leukemia viruses;epithelial morphogenesis;pathogenesis of leukemia, MDS, myeloproliferative neoplasms, and congenital neutropenia;cell cycle control;programmed cell death in development and malignancy. Completion of this program will prepare talented trainees for careers in basic and translational hematology research, to make discoveries that will transform the diagnosis and treatment of hematologic diseases.
Funding Period: 1975-07-01 - 2016-02-29
more information: NIH RePORT

Top Publications

  1. ncbi Inositol polyphosphate multikinase regulates inositol 1,4,5,6-tetrakisphosphate
    Shao Chun Chang
    Department of Internal Medicine, Division of Hematology, Box 8125, Washington University, School of Medicine, St Louis, MO 63110, USA
    Biochem Biophys Res Commun 339:209-16. 2006
  2. pmc The LIM protein LIMD1 influences osteoblast differentiation and function
    Hilary F Luderer
    Department of Cell Biology, Washington University School of Medicine, St Louis, MO 63110, USA
    Exp Cell Res 314:2884-94. 2008
  3. pmc Cargo-sorting signals promote polymerization of adaptor protein-1 in an Arf-1.GTP-independent manner
    Intaek Lee
    Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
    Arch Biochem Biophys 479:63-8. 2008
  4. pmc Integrated genomic analysis implicates haploinsufficiency of multiple chromosome 5q31.2 genes in de novo myelodysplastic syndromes pathogenesis
    Timothy A Graubert
    Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, Missouri, United States of America
    PLoS ONE 4:e4583. 2009
  5. pmc Genome-wide association study to identify novel loci associated with therapy-related myeloid leukemia susceptibility
    Jeffrey A Knight
    Committee on Cancer Biology, University of Chicago, IL 60637, USA
    Blood 113:5575-82. 2009
  6. pmc The bisphosphonate zoledronic acid decreases tumor growth in bone in mice with defective osteoclasts
    Angela C Hirbe
    Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St Louis, MO 63110, USA
    Bone 44:908-16. 2009
  7. pmc UDP-GlcNAc:Glycoprotein N-acetylglucosamine-1-phosphotransferase mediates the initial step in the formation of the methylphosphomannosyl residues on the high mannose oligosaccharides of Dictyostelium discoideum glycoproteins
    Yi Qian
    Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
    Biochem Biophys Res Commun 393:678-81. 2010
  8. pmc A protease-resistant PML-RAR{alpha} has increased leukemogenic potential in a murine model of acute promyelocytic leukemia
    Geoffrey L Uy
    Section of Stem Cell Biology, Division of Oncology, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA
    Blood 116:3604-10. 2010
  9. pmc Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression
    Lukas D Wartman
    Department of Internal Medicine, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St Louis, Missouri, USA
    J Clin Invest 121:1445-55. 2011
  10. pmc CD8+ T cells regulate bone tumor burden independent of osteoclast resorption
    Kaihua Zhang
    Department of Orthopedics, Washington University School of Medicine, St Louis, MO 63110, USA
    Cancer Res 71:4799-808. 2011

Detail Information

Publications31

  1. ncbi Inositol polyphosphate multikinase regulates inositol 1,4,5,6-tetrakisphosphate
    Shao Chun Chang
    Department of Internal Medicine, Division of Hematology, Box 8125, Washington University, School of Medicine, St Louis, MO 63110, USA
    Biochem Biophys Res Commun 339:209-16. 2006
    ..Hence, the human 5-kinase may also regulate the level of Ins(1,4,5,6)P4 and have an effect on chloride channel regulation...
  2. pmc The LIM protein LIMD1 influences osteoblast differentiation and function
    Hilary F Luderer
    Department of Cell Biology, Washington University School of Medicine, St Louis, MO 63110, USA
    Exp Cell Res 314:2884-94. 2008
    ..Together, these data identify Limd1 as a novel regulator of both bone osetoclast and bone osteoblast development and function...
  3. pmc Cargo-sorting signals promote polymerization of adaptor protein-1 in an Arf-1.GTP-independent manner
    Intaek Lee
    Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
    Arch Biochem Biophys 479:63-8. 2008
    ..GTP and membranes are not required for this process. We propose that cargo-induced polymerization of AP-1 contributes to stabilization of the coat complex in the formation of clathrin-coated buds...
  4. pmc Integrated genomic analysis implicates haploinsufficiency of multiple chromosome 5q31.2 genes in de novo myelodysplastic syndromes pathogenesis
    Timothy A Graubert
    Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, Missouri, United States of America
    PLoS ONE 4:e4583. 2009
    ..2 genes are not common events in MDS, and implicate haploinsufficiency of multiple genes as the relevant genetic consequence of this common deletion...
  5. pmc Genome-wide association study to identify novel loci associated with therapy-related myeloid leukemia susceptibility
    Jeffrey A Knight
    Committee on Cancer Biology, University of Chicago, IL 60637, USA
    Blood 113:5575-82. 2009
    ..Thus, we conclude that the effect of genetic factors contributing to cancer risk is potentiated and more readily discernable in t-AML compared with sporadic cancer...
  6. pmc The bisphosphonate zoledronic acid decreases tumor growth in bone in mice with defective osteoclasts
    Angela C Hirbe
    Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St Louis, MO 63110, USA
    Bone 44:908-16. 2009
    ..OC-defective mice treated with ZA demonstrated a significant 88% decrease in tumor growth in bone compared to vehicle-treated OC-defective mice. These data support an osteoclast-independent role for N-BP therapy in bone metastasis...
  7. pmc UDP-GlcNAc:Glycoprotein N-acetylglucosamine-1-phosphotransferase mediates the initial step in the formation of the methylphosphomannosyl residues on the high mannose oligosaccharides of Dictyostelium discoideum glycoproteins
    Yi Qian
    Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
    Biochem Biophys Res Commun 393:678-81. 2010
    ..We conclude that the gpt1 gene product catalyzes the initial step in the formation of methylphosphomannosyl residues on D. discoideum lysosomal hydrolases...
  8. pmc A protease-resistant PML-RAR{alpha} has increased leukemogenic potential in a murine model of acute promyelocytic leukemia
    Geoffrey L Uy
    Section of Stem Cell Biology, Division of Oncology, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA
    Blood 116:3604-10. 2010
    ..Together, these effects appear to increase the leukemogenicity of NE-resistant PR, contrary to our previous prediction. We conclude that NE deficiency may reduce APL penetrance via indirect mechanisms that are still NE dependent...
  9. pmc Sequencing a mouse acute promyelocytic leukemia genome reveals genetic events relevant for disease progression
    Lukas D Wartman
    Department of Internal Medicine, Division of Oncology, Stem Cell Biology Section, Washington University School of Medicine, Siteman Cancer Center, St Louis, Missouri, USA
    J Clin Invest 121:1445-55. 2011
    ..In conclusion, whole genome sequencing of mouse cancer genomes can provide an unbiased and comprehensive approach for discovering functionally relevant mutations that are also present in human leukemias...
  10. pmc CD8+ T cells regulate bone tumor burden independent of osteoclast resorption
    Kaihua Zhang
    Department of Orthopedics, Washington University School of Medicine, St Louis, MO 63110, USA
    Cancer Res 71:4799-808. 2011
    ..Our findings show the important contribution of CD8(+) T cells in the regulation of bone metastases regardless of OC status, thus including T cells as critical regulators of tumor growth in bone...
  11. pmc The ADP receptor P2RY12 regulates osteoclast function and pathologic bone remodeling
    Xinming Su
    Department of Medicine, Division of Oncology, Washington University in St Louis School of Medicine, St Louis, Missouri 63110, USA
    J Clin Invest 122:3579-92. 2012
    ..These results demonstrate that P2RY12 is the primary ADP receptor in OCs and suggest that P2RY12 inhibition is a potential therapeutic target for pathologic bone loss...
  12. pmc Quantitative proteomics with siRNA screening identifies novel mechanisms of trastuzumab resistance in HER2 amplified breast cancers
    Alaina P Boyer
    Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
    Mol Cell Proteomics 12:180-93. 2013
    ..These proteins may present targets for the development of clinical diagnostics or therapeutic strategies to guide the treatment of HER2+ breast cancer patients who develop trastuzumab resistance...
  13. pmc Notch signaling in acute promyelocytic leukemia
    N R Grieselhuber
    Section of Stem Cell Biology, Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
    Leukemia 27:1548-57. 2013
    ..These findings expand the role of Notch signaling in hematopoietic diseases, and further define the mechanistic events important for PML-RARA-mediated leukemogenesis. ..
  14. pmc Carboxyl group footprinting mass spectrometry and molecular dynamics identify key interactions in the HER2-HER3 receptor tyrosine kinase interface
    Timothy S Collier
    Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Biol Chem 288:25254-64. 2013
    ..This study provides valuable insights into the EGF receptor/HER/ErbB kinase structure and interactions, which can guide the design of future therapies. ..
  15. pmc Regulation of Chk2 ubiquitination and signaling through autophosphorylation of serine 379
    Christine M Lovly
    Department of Cell Biology and Physiology, Washington University School of Medicine, Box 8228, 660 S Euclid Ave, St Louis, MO 63110, USA
    Mol Cell Biol 28:5874-85. 2008
    ..Importantly, S379 was required for Chk2 to induce apoptosis in cells with DNA double-strand breaks. Thus, auto-/transphosphorylation of S379 is required for Chk2 ubiquitination and effector function...
  16. ncbi Pulmonary arterial hypertension and left-sided heart disease in sickle cell disease: clinical characteristics and association with soluble adhesion molecule expression
    Elizabeth S Klings
    The Pulmonary Center, Boston University School of Medicine, Boston, Massachusetts 02118, USA
    Am J Hematol 83:547-53. 2008
    ....
  17. pmc RelB is the NF-kappaB subunit downstream of NIK responsible for osteoclast differentiation
    Sergio Vaira
    Division of Bone and Mineral Diseases, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
    Proc Natl Acad Sci U S A 105:3897-902. 2008
    ..Thus, the alternative NF-kappaB pathway, culminating in activation of RelB, has a key and specific role in the differentiation of OCs that cannot be compensated for by p65...
  18. pmc COG-7-deficient Human Fibroblasts Exhibit Altered Recycling of Golgi Proteins
    Richard Steet
    Department of Internal Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
    Mol Biol Cell 17:2312-21. 2006
    ..These results serve to better define the role of the COG complex in facilitating protein trafficking between the Golgi and ER and provide a diagnostic framework for the identification of CDG defects involving trafficking proteins...
  19. ncbi Accurate mass-driven analysis for the characterization of protein phosphorylation. Study of the human Chk2 protein kinase
    Julie B King
    Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    Anal Chem 78:2171-81. 2006
    ..Thus, accurate mass-driven analysis and rapid parallel MS/MS acquisition is a useful method for the discovery of new phosphorylation sites that is independent of the signature losses from phosphorylated amino acid residues...
  20. pmc Angiogenic cells can be rapidly mobilized and efficiently harvested from the blood following treatment with AMD3100
    Rebecca M Shepherd
    Division of Oncology, Department of Medicine, 660 S Euclid Ave, Campus Box 8007, Saint Louis, MO 63110, USA
    Blood 108:3662-7. 2006
    ..These data show that AMD3100 is a potent and rapid mobilizer of angiogenic cells and demonstrate the feasibility of obtaining and storing large numbers of angiogenic cells by leukapheresis...
  21. ncbi The number of endothelial progenitor cell colonies in the blood is increased in patients with angiographically significant coronary artery disease
    Hasan Guven
    Division of Cardiology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Am Coll Cardiol 48:1579-87. 2006
    ....
  22. pmc Granulocyte colony-stimulating factor enhances bone tumor growth in mice in an osteoclast-dependent manner
    Angela C Hirbe
    Department of Medicine and Division of Oncology, Washington University School of Medicine, 660 S Euclid Avenue, St Louis, MO 63110, USA
    Blood 109:3424-31. 2007
    ..These data demonstrate a G-CSF-induced stimulation of tumor growth in bone that is OC dependent...
  23. pmc Myeloproliferative disease induced by TEL-PDGFRB displays dynamic range sensitivity to Stat5 gene dosage
    Jennifer A Cain
    Department of Internal Medicine, Division of Oncology, Washington University Siteman Cancer Center, 550 S Euclid Avenue, St Louis, MO 63110, USA
    Blood 109:3906-14. 2007
    ..Together, these data demonstrate that Stat5a and Stat5b are dose-limiting mediators of TEL-PDGFRB-induced myeloproliferation...
  24. ncbi Identification of oxidative post-translational modification of serum albumin in patients with idiopathic pulmonary arterial hypertension and pulmonary hypertension of sickle cell anemia
    Adam Odhiambo
    The Pulmonary Center, Boston University School of Medicine, Boston, MA 02118, USA
    Rapid Commun Mass Spectrom 21:2195-203. 2007
    ..This finding supports the notion that oxidative stress modulates the pathogenesis of PH of SCA and suggests that this and other post-translational modifications may be important biomarkers of disease...
  25. pmc Lentiviral-mediated RNAi inhibition of Sbds in murine hematopoietic progenitors impairs their hematopoietic potential
    Amy S Rawls
    Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA
    Blood 110:2414-22. 2007
    ..These data provide the first evidence that loss of Sbds is sufficient to induce abnormalities in hematopoiesis...
  26. pmc Development of sensory, motor and behavioral deficits in the murine model of Sanfilippo syndrome type B
    Coy D Heldermon
    Washington University in St Louis, School of Medicine, St Louis, Missouri, United States of America
    PLoS ONE 2:e772. 2007
    ..The murine model of MPS IIIB demonstrates lysosomal distention in multiple tissues, a shortened life span, and behavioral changes...
  27. pmc Disruption of CXCR4 enhances osteoclastogenesis and tumor growth in bone
    Angela C Hirbe
    Department of Medicine, Division of Oncology, Washington University School of Medicine, 660 South Euclid Avenue, St Louis, MO 63110, USA
    Proc Natl Acad Sci U S A 104:14062-7. 2007
    ..These data demonstrate that disruption of CXCR4 enhances osteoclastogenesis and suggest that inhibition of CXCR4 may enhance established skeletal tumor burden by increasing OC activity...
  28. pmc Mutations of the ELA2 gene found in patients with severe congenital neutropenia induce the unfolded protein response and cellular apoptosis
    David S Grenda
    Division of Oncology, Washington University School of Medicine, St Louis, MO 63110, USA
    Blood 110:4179-87. 2007
    ..Collectively, these data provide strong support for a UPR model of SCN disease pathogenesis and place SCN in a growing list of human diseases caused by misfolded proteins...
  29. pmc Erythrocyte glutamine depletion, altered redox environment, and pulmonary hypertension in sickle cell disease
    Claudia R Morris
    Department of Emergency Medicine, Children s Hospital and Research Center Oakland, 747 52nd St, Oakland, CA 94609, USA
    Blood 111:402-10. 2008
    ..Decreased erythrocyte glutathione and glutamine levels contribute to alterations in the erythrocyte redox environment, which may compromise erythrocyte integrity, contribute to hemolysis, and play a role in the pathogenesis of PH of SCD...
  30. pmc APT102, a novel adpase, cooperates with aspirin to disrupt bone metastasis in mice
    Ozge Uluçkan
    Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, Missouri 63110, USA
    J Cell Biochem 104:1311-23. 2008
    ..Anti-platelet drugs such as ASA + APT102 could be valuable experimental tools for studying the role of platelet activation in metastasis as well as a therapeutic option for the prevention of bone metastases...
  31. pmc The DNA double-strand break response is abnormal in myeloblasts from patients with therapy-related acute myeloid leukemia
    M A Jacoby
    Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO, USA
    Leukemia 28:1242-51. 2014
    ....