A Center of Molecular Developmental Hematopoiesis: The Center of Excellence in Molecular Hematology was established ~15 years ago by the Principal Investigator (S.H. Orkin) and the co-investigator (L.I. Zon). The Center was based on the premise that parallel genetic investigation of the major vertebrate model organisms, mice and zebrafish, would advance our understanding of fundamental aspects of blood cell formation, provide a platform for new insights into disease, and stimulate broader hematological research among our colleagues and trainees. Moreover, the work of the Center, we hoped, would provide fundamental results that could be translated to the treatment of clinical problems. Our experience, we believe, validates the original premise. The Center has provided a focus for research activities and greatly benefited the research community through the services provided by its Cores. Two Cores have remained constant since the Center's inception. CORE A is a Mouse Embryonic Stem (ES) Cell and Gene Targeting Core that has supported investigators through education and consultation, oocyte and blastocyst microinjections, assistance in embryo and hematological phenotyping, and de novo ES cell derivation. The menu of available services provided extends well beyond that offered by conventional mouse cores. CORE B is a zebrafish core that serves investigators both locally and internationally. CORE B maintains numerous mutant strains, as well as unique strains (such as transparent Casper fish). CORE B has been instrumental in supporting zebrafish screening efforts and also the work of junior, emerging investigators as well as researchers from other disciplines who seek to use the zebrafish as a model organism. CORE C has traditionally provided resources for rapid genetic mapping of zebrafish genes and bioinformatics analysis. With the maturity of the zebrafish genome project and general availability of informatics support in the Harvard Medical area, we have decided in the current renewal application to redirect the focus of CORE C to provide technological support to investigators in two critical areas. First, CORE C will house and further develop a newly established flow cytometry (FACS) core that provides fee-for-service analysis and isolation of cell populations. Second, CORE C will provide a new service to the community: validation of antibodies and methodologies for chromatin immunoprecipitation (ChIP) and ChlP-chip or ChIP sequencing. In parallel, CORE C will explore and then disseminate approaches to minimize sample size in an effort to facilitate genomic and epigenetic studies on limited populations, such as HSCs. Access to the services of the Center is available to virtually all investigators who approach the Center with research projects that fall within the broad umbrella of hematology research and can be enhanced by the services provided. We have a non-exclusive view of membership. Except for FACS analysis and cell preparation, all services are without charge.
Our aim i s to encourage use of the resources of the Center and to eliminate barriers to investigators, particularly to junior investigators. To date, we have been able to manage the demand for services.

Public Health Relevance

Research in the area of developmental molecular hematology is fundamental to an improved understanding of disorders affecting blood cell production and function. Such research is central to the mission of the NIDDK hematology program.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Center Core Grants (P30)
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Special Emphasis Panel (ZDK1-GRB-G (O3))
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Bishop, Terry Rogers
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Children's Hospital Boston
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Vo, Linda T; Kinney, Melissa A; Liu, Xin et al. (2018) Regulation of embryonic haematopoietic multipotency by EZH1. Nature 553:506-510
Mandelbaum, Joseph; Shestopalov, Ilya A; Henderson, Rachel E et al. (2018) Zebrafish blastomere screen identifies retinoic acid suppression of MYB in adenoid cystic carcinoma. J Exp Med 215:2673-2685
Yamauchi, Takuji; Masuda, Takeshi; Canver, Matthew C et al. (2018) Genome-wide CRISPR-Cas9 Screen Identifies Leukemia-Specific Dependence on a Pre-mRNA Metabolic Pathway Regulated by DCPS. Cancer Cell 33:386-400.e5
Blaser, Bradley W; Zon, Leonard I (2018) Making HSCs in vitro: don't forget the hemogenic endothelium. Blood 132:1372-1378
Cesana, Marcella; Guo, Michael H; Cacchiarelli, Davide et al. (2018) A CLK3-HMGA2 Alternative Splicing Axis Impacts Human Hematopoietic Stem Cell Molecular Identity throughout Development. Cell Stem Cell 22:575-588.e7
Blaser, Bradley W; Moore, Jessica L; Hagedorn, Elliott J et al. (2017) CXCR1 remodels the vascular niche to promote hematopoietic stem and progenitor cell engraftment. J Exp Med 214:1011-1027
Perlin, Julie R; Robertson, Anne L; Zon, Leonard I (2017) Efforts to enhance blood stem cell engraftment: Recent insights from zebrafish hematopoiesis. J Exp Med 214:2817-2827
Doulatov, Sergei; Vo, Linda T; Macari, Elizabeth R et al. (2017) Drug discovery for Diamond-Blackfan anemia using reprogrammed hematopoietic progenitors. Sci Transl Med 9:
Lessard, Samuel; Francioli, Laurent; Alfoldi, Jessica et al. (2017) Human genetic variation alters CRISPR-Cas9 on- and off-targeting specificity at therapeutically implicated loci. Proc Natl Acad Sci U S A 114:E11257-E11266
Perlin, Julie R; Sporrij, Audrey; Zon, Leonard I (2017) Blood on the tracks: hematopoietic stem cell-endothelial cell interactions in homing and engraftment. J Mol Med (Berl) 95:809-819

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