Leonard I Zon

Howard Hughes Medical Institute, Ашбърн, Virginia, United States

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Publications (442)4686.37 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Rare endothelial cells in the aorta-gonad-mesonephros (AGM) transition into hematopoietic stem cells (HSCs) during embryonic development. Lineage tracing experiments indicate that HSCs emerge from Cadherin 5 (Cdh5, VE-cadherin)(+) endothelial precursors, and isolated populations of Cdh5(+) cells from mouse embryos and embryonic stem (ES) cells can be differentiated into hematopoietic cells. Cdh5 has also been widely implicated as a marker of AGM-derived hemogenic endothelial cells. Since Cdh5(-/-) mice embryos die before the first HSCs emerge, it is unknown if Cdh5 has a direct role in HSC emergence. Our previous genetic screen yielded malbec (mlb(bw306)), a zebrafish mutant for cdh5, with normal embryonic and definitive blood. Utilizing time-lapse confocal imaging, parabiotic surgical pairing of zebrafish embryos, and blastula transplantation assays, we show that HSCs emerge, migrate, engraft, and differentiate in the absence of cdh5 expression. By tracing Cdh5(-/-)GFP(+/+) cells in chimeric mice, we demonstrated that Cdh5(-/-) GFP(+/+) HSCs emerging from E10.5 and E11.5 AGM or derived from E13.5 fetal liver not only differentiate into hematopoietic colonies but also engraft and reconstitute multi-lineage adult blood. We also developed a conditional mouse Cdh5 knockout (Cdh5(flox/flox):Scl-Cre-ER(T)) and demonstrated that multipotent hematopoietic colonies form despite the absence of Cdh5. These data establish that Cdh5, a marker of hemogenic endothelium in the AGM, is dispensable for the transition of hemogenic endothelium to HSCs.
    Blood 09/2015; DOI:10.1182/blood-2015-07-659276 · 10.45 Impact Factor
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    ABSTRACT: The vertebrate heart develops from two distinct lineages of cardiomyocytes that arise from the first and second heart fields (FHF and SHF, respectively). The FHF forms the primitive heart tube, while adding cells from the SHF allow elongation at both poles of the tube. Initially seen as an exclusive characteristic of higher vertebrates, recent work has demonstrated the presence of a distinct FHF and SHF in lower vertebrates, including zebrafish. We found that key transcription factors that regulate septation and chamber formation in higher vertebrates, including Tbx5 and Pitx2, influence relative FHF and SHF contributions to the zebrafish heart tube. To identify molecular modulators of heart field migration, we used microarray-based expression profiling following inhibition of tbx5a and pitx2ab in embryonic zebrafish (Mosimann & Panakova, et al, 2015; GSE70750). Here, we describe in more detail the procedure used to process, prioritize, and analyze the expression data for functional enrichment.
    Genomics Data 09/2015; 6. DOI:10.1016/j.gdata.2015.09.015
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    ABSTRACT: The vertebrate heart muscle (myocardium) develops from the first heart field (FHF) and expands by adding second heart field (SHF) cells. While both lineages exist already in teleosts, the primordial contributions of FHF and SHF to heart structure and function remain incompletely understood. Here we delineate the functional contribution of the FHF and SHF to the zebrafish heart using the cis-regulatory elements of the draculin (drl) gene. The drl reporters initially delineate the lateral plate mesoderm, including heart progenitors. Subsequent myocardial drl reporter expression restricts to FHF descendants. We harnessed this unique feature to uncover that loss of tbx5a and pitx2 affect relative FHF versus SHF contributions to the heart. High-resolution physiology reveals distinctive electrical properties of each heart field territory that define a functional boundary within the single zebrafish ventricle. Our data establish that the transcriptional program driving cardiac septation regulates physiologic ventricle partitioning, which successively provides mechanical advantages of sequential contraction.
    Nature Communications 08/2015; 6:8146. DOI:10.1038/ncomms9146 · 11.47 Impact Factor
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    ABSTRACT: Metastasis is the defining feature of advanced malignancy, yet remains challenging to study in laboratory environments. Here we describe a high-throughput zebrafish system for comprehensive, in vivo assessment of metastatic biology. First, we generated several stable cell lines from melanomas of transgenic mitfa-BRAFV600E;p53-/- fish. We then transplanted the melanoma cells into the transparent casper strain to enable highly quantitative measurement of the metastatic process at single cell resolution. Using computational image analysis of the resulting metastases, we generated a metastasis score, µ, that can be applied to quantitative comparison of metastatic capacity between experimental conditions. Furthermore, image analysis also provided estimates of the frequency of metastasis-initiating cells (~1/120,000 cells). Finally, we determined that the degree of pigmentation is a key feature defining cells with metastatic capability. The small size and rapid generation of progeny combined with superior imaging tools make zebrafish ideal for unbiased high-throughput investigations of cell-intrinsic or microenvironmental modifiers of metastasis. The approaches described here are readily applicable to other tumor types and thus serve to complement studies also employing murine and human cell culture systems. Copyright © 2015, American Association for Cancer Research.
    Cancer Research 08/2015; 75(20). DOI:10.1158/0008-5472.CAN-14-3319 · 9.33 Impact Factor

  • Cancer Research 08/2015; 75(15 Supplement):5152-5152. DOI:10.1158/1538-7445.AM2015-5152 · 9.33 Impact Factor
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    ABSTRACT: The use of human pluripotent stem cells for in vitro disease modelling and clinical applications requires protocols that convert these cells into relevant adult cell types. Here, we report the rapid and efficient differentiation of human pluripotent stem cells into vascular endothelial and smooth muscle cells. We found that GSK3 inhibition and BMP4 treatment rapidly committed pluripotent cells to a mesodermal fate and subsequent exposure to VEGF-A or PDGF-BB resulted in the differentiation of either endothelial or vascular smooth muscle cells, respectively. Both protocols produced mature cells with efficiencies exceeding 80% within six days. On purification to 99% via surface markers, endothelial cells maintained their identity, as assessed by marker gene expression, and showed relevant in vitro and in vivo functionality. Global transcriptional and metabolomic analyses confirmed that the cells closely resembled their in vivo counterparts. Our results suggest that these cells could be used to faithfully model human disease.
    Nature Cell Biology 07/2015; 17(8). DOI:10.1038/ncb3205 · 19.68 Impact Factor
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    ABSTRACT: Haematopoietic stem and progenitor cell (HSPC) transplant is a widely used treatment for life-threatening conditions such as leukaemia; however, the molecular mechanisms regulating HSPC engraftment of the recipient niche remain incompletely understood. Here we develop a competitive HSPC transplant method in adult zebrafish, using in vivo imaging as a non-invasive readout. We use this system to conduct a chemical screen, and identify epoxyeicosatrienoic acids (EETs) as a family of lipids that enhance HSPC engraftment. The pro-haematopoietic effects of EETs were conserved in the developing zebrafish embryo, where 11,12-EET promoted HSPC specification by activating a unique activator protein 1 (AP-1) and runx1 transcription program autonomous to the haemogenic endothelium. This effect required the activation of the phosphatidylinositol-3-OH kinase (PI(3)K) pathway, specifically PI(3)Kγ. In adult HSPCs, 11,12-EET induced transcriptional programs, including AP-1 activation, which modulate several cellular processes, such as migration, to promote engraftment. Furthermore, we demonstrate that the EET effects on enhancing HSPC homing and engraftment are conserved in mammals. Our study establishes a new method to explore the molecular mechanisms of HSPC engraftment, and discovers a previously unrecognized, evolutionarily conserved pathway regulating multiple haematopoietic generation and regeneration processes. EETs may have clinical application in marrow or cord blood transplantation.
    Nature 07/2015; 523(7561):468-71. DOI:10.1038/nature14569 · 41.46 Impact Factor
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    ABSTRACT: Dysregulation of ribosome biogenesis causes human diseases, such as Diamond-Blackfan anemia, del (5q-) syndrome and bone marrow failure. However, the mechanisms of blood disorders in these diseases remain elusive. Through genetic mapping, molecular cloning and mechanism characterization of the zebrafish mutant cas002, we reveal a novel connection between ribosomal dysfunction and excessive autophagy in the regulation of hematopoietic stem/progenitor cells (HSPCs). cas002 carries a recessive lethal mutation in kri1l gene that encodes an essential component of rRNA small subunit processome. We show that Kri1l is required for normal ribosome biogenesis, expansion of definitive HSPCs and subsequent lineage differentiation. Through live imaging and biochemical studies, we find that loss of Kri1l causes the accumulation of misfolded proteins and excessive PERK activation-dependent autophagy in HSPCs. Blocking autophagy but not inhibiting apoptosis by Bcl2 overexpression can fully rescue hematopoietic defects, but not the lethality of kri1l(cas002) embryos. Treatment with autophagy inhibitors (3-MA and Baf A1) or PERK inhibitor (GSK2656157), or knockdown of beclin1 or perk can markedly restore HSPC proliferation and definitive hematopoietic cell differentiation. These results may provide leads for effective therapeutics that benefit patients with anemia or bone marrow failure caused by ribosome disorders.Cell Research advance online publication 3 July 2015; doi:10.1038/cr.2015.81.
    Cell Research 07/2015; 25(8). DOI:10.1038/cr.2015.81 · 12.41 Impact Factor
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    ABSTRACT: In vertebrate definitive hematopoiesis, nascent hematopoietic stem/progenitor cells (HSPCs) migrate to and reside in proliferative hematopoietic microenvironment for transitory expansion. In this process, well-established DNA damage response pathways are vital to resolve the replication stress, which is deleterious for genome stability and cell survival. However, the detailed mechanism on the response and repair of the replication stress-induced DNA damage during hematopoietic progenitor expansion remains elusive. Here we report that a novel zebrafish mutantcas003 with nonsense mutation in topbp1 gene encoding topoisomerase II β binding protein 1 (TopBP1) exhibits severe definitive hematopoiesis failure. Homozygous topbp1cas003 mutants manifest reduced number of HSPCs during definitive hematopoietic cell expansion, without affecting the formation and migration of HSPCs. Moreover, HSPCs in the caudal hematopoietic tissue (an equivalent of the fetal liver in mammals) in topbp1cas003 mutant embryos are more sensitive to hydroxyurea (HU) treatment. Mechanistically, subcellular mislocalization of TopBP1cas003 protein results in ATR/Chk1 activation failure and DNA damage accumulation in HSPCs, and eventually induces the p53-dependent apoptosis of HSPCs. Collectively, this study demonstrates a novel and vital role of TopBP1 in the maintenance of HSPCs genome integrity and survival during hematopoietic progenitor expansion.
    PLoS Genetics 07/2015; 11(7):e1005346. DOI:10.1371/journal.pgen.1005346 · 7.53 Impact Factor
  • X Peng · M Dong · L Ma · X-E Jia · J Mao · C Jin · Y Chen · L Gao · X Liu · K Ma · [...] · T Du · Y Jin · Q Huang · K Li · L I Zon · T Liu · M Deng · Y Zhou · X Xi · S Chen ·
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    ABSTRACT: Controlled self-renewal and differentiation of hematopoietic stem/progenitor cells (HSPCs) are critical for vertebrate development and survival. These processes are tightly regulated by the transcription factors, signaling molecules, and epigenetic factors. Impaired regulations of their function could result in hematological malignancies. Using a large-scale zebrafish N-ethyl-N-nitrosourea (ENU) mutagenesis screening, we identified a line named LDD731, which presented significantly increased HSPCs in hematopoietic organs. Further analysis revealed that the erythoid/myeloid lineages in definitive hematopoiesis were increased while the primitive hematopoiesis was not affected. The homozygous mutation was lethal with a median survival time around 14-15 days post-fertilization. The causal mutation was located by positional cloning in the c-cbl gene, of which the human ortholog, c-CBL, is found frequently mutated in myeloproliferative neoplasms (MPN) or acute leukemia. Sequence analysis showed the mutation in LDD731 caused a histidine-to-tyrosine substitution of the amino acid (aa) codon 382 within the RING finger domain of c-Cbl. Moreover, the myeloproliferative phenotype in zebrafish seemed dependent on the Flt3 (fms-like tyrosine kinase 3) signaling, consistent with that observed in both mice and humans. Our study may shed new lights on the pathogenesis of MPN and provide a useful in vivo vertebrate model for drug screenings for this syndrome.Leukemia accepted article preview online, 24 June 2015. doi:10.1038/leu.2015.154.
    Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 06/2015; DOI:10.1038/leu.2015.154 · 10.43 Impact Factor
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    ABSTRACT: Fluid shear stress promotes the emergence of hematopoietic stem cells (HSCs) in the aorta-gonad-mesonephros (AGM) of the developing mouse embryo. We determined that the AGM is enriched for expression of targets of protein kinase A (PKA)-cAMP response element-binding protein (CREB), a pathway activated by fluid shear stress. By analyzing CREB genomic occupancy from chromatin-immunoprecipitation sequencing (ChIP-seq) data, we identified the bone morphogenetic protein (BMP) pathway as a potential regulator of CREB. By chemical modulation of the PKA-CREB and BMP pathways in isolated AGM VE-cadherin(+) cells from mid-gestation embryos, we demonstrate that PKA-CREB regulates hematopoietic engraftment and clonogenicity of hematopoietic progenitors, and is dependent on secreted BMP ligands through the type I BMP receptor. Finally, we observed blunting of this signaling axis using Ncx1-null embryos, which lack a heartbeat and intravascular flow. Collectively, we have identified a novel PKA-CREB-BMP signaling pathway downstream of shear stress that regulates HSC emergence in the AGM via the endothelial-to-hematopoietic transition. © 2015 Kim et al.
    Journal of Experimental Medicine 04/2015; 209(2). DOI:10.1084/jem.20141514 · 12.52 Impact Factor
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    ABSTRACT: Hematopoietic stem cells (HSCs) emerge from aortic endothelium via the endothelial-to-hematopoietic transition (EHT). The molecular mechanisms that initiate and regulate EHT remain poorly understood. Here, we show that adenosine signaling regulates hematopoietic stem and progenitor cell (HSPC) development in zebrafish embryos. The adenosine receptor A2b is expressed in the vascular endothelium before HSPC emergence. Elevated adenosine levels increased runx1(+)/cmyb(+) HSPCs in the dorsal aorta, whereas blocking the adenosine pathway decreased HSPCs. Knockdown of A2b adenosine receptor disrupted scl(+) hemogenic vascular endothelium and the subsequent EHT process. A2b adenosine receptor activation induced CXCL8 via cAMP-protein kinase A (PKA) and mediated hematopoiesis. We further show that adenosine increased multipotent progenitors in a mouse embryonic stem cell colony-forming assay and in embryonic day 10.5 aorta-gonad-mesonephros explants. Our results demonstrate that adenosine signaling plays an evolutionary conserved role in the first steps of HSPC formation in vertebrates. © 2015 Jing et al.
    Journal of Experimental Medicine 04/2015; 209(2). DOI:10.1084/jem.20141528 · 12.52 Impact Factor

  • Leukemia Research 04/2015; 39:S11. DOI:10.1016/S0145-2126(15)30026-6 · 2.35 Impact Factor
  • Julien Ablain · Ellen M Durand · Song Yang · Yi Zhou · Leonard I Zon ·
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    ABSTRACT: CRISPR/Cas9 technology of genome editing has greatly facilitated the targeted inactivation of genes in vitro and in vivo in a wide range of organisms. In zebrafish, it allows the rapid generation of knockout lines by simply injecting a guide RNA (gRNA) and Cas9 mRNA into one-cell stage embryos. Here, we report a simple and scalable CRISPR-based vector system for tissue-specific gene inactivation in zebrafish. As proof of principle, we used our vector with the gata1 promoter driving Cas9 expression to silence the urod gene, implicated in heme biosynthesis, specifically in the erythrocytic lineage. Urod targeting yielded red fluorescent erythrocytes in zebrafish embryos, recapitulating the phenotype observed in the yquem mutant. While F0 embryos displayed mosaic gene disruption, the phenotype appeared very penetrant in stable F1 fish. This vector system constitutes a unique tool to spatially control gene knockout and greatly broadens the scope of loss-of-function studies in zebrafish. Copyright © 2015 Elsevier Inc. All rights reserved.
    Developmental Cell 03/2015; 32(6). DOI:10.1016/j.devcel.2015.01.032 · 9.71 Impact Factor
  • Michelle Dang · Leonard I. Zon ·
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    ABSTRACT: Metastatic melanoma is an aggressive disease that historically has had very limited therapeutic options. FDA approved BRAF and MEK inhibitors are now used to successfully treat mutant BRAF(V) (600E) -driven human melanomas; however, the efficacy is short-lived, and patients generally develop resistance within a year. Immunotherapies are also promising, but predicting responses is still difficult and side effects can be severe. As there is no effective secondary line of treatment for patients with BRAF/MEK-inhibitor drug-resistant melanomas, there is a major unmet clinical need to identify mechanisms of drug resistance and develop novel drug combinations to prevent or delay resistance. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Pigment Cell & Melanoma Research 03/2015; 28(4). DOI:10.1111/pcmr.12368 · 4.62 Impact Factor
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    ABSTRACT: Angiopoietin-like proteins (angptls) are capable of ex vivo expansion of mouse and human hematopoietic stem and progenitor cells (HSPCs). Despite this intriguing ability, their mechanism is unknown. Here, we show that angptl2 overexpression is sufficient to expand definitive HSPCs in zebrafish embryos. Angptl1/2 are required for definitive hematopoiesis and vascular specification of the hemogenic endothelium. The loss-of-function phenotype is reminiscent of the notch mutant mindbomb (mib) and a strong genetic interaction occurs between angptls and notch. Overexpressing angptl2 rescues mib while overexpressing notch rescues angptl1/2 morphants. Gene expression studies in Angptl2-stimulated CD34(+) cells showed a strong Myc activation signature and myc overexpression in angptl1/2 morphants or mib restored HSPCs formation. Angptl2 can increase Notch activation in cultured cells and Angptl receptor interacted with Notch to regulate Notch cleavage. Together our data provide insight to the angptl-mediated notch activation through receptor interaction and subsequent activation of myc targets.
    eLife Sciences 02/2015; 4(4). DOI:10.7554/eLife.05544 · 9.32 Impact Factor
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    ABSTRACT: DNA methyltransferase 1 (Dnmt1) regulates expression of many critical genes through maintaining parental DNA methylation patterns on daughter DNA strands during mitosis. It is essential for embryonic development and diverse biological processes, including maintenance of hematopoietic stem and progenitor cells (HSPCs). However, the precise molecular mechanism of how Dnmt1 is involved in HSPC maintenance remains unexplored. An N-ethyl-N-nitrosourea (ENU)-based genetic screening was performed to identify putative mutants with defects in definitive HSPCs during hematopoiesis in zebrafish. The expression of hematopoietic markers was analyzed via whole mount in situ hybridization assay (WISH). Positional cloning approach was carried out to identify the gene responsible for the defective definitive hematopoiesis in the mutants. Analyses of the mechanism were conducted by morpholino-mediated gene knockdown, mRNA injection rescue assays, anti-phosphorylated histone H3 (pH3) immunostaining and TUNEL assay, quantitative real-time PCR, and bisulfite sequencing analysis. A heritable mutant line with impaired HSPCs of definitive hematopoiesis was identified. Positional cloning demonstrated that a stop codon mutation was introduced in dnmt1 which resulted in a predicted truncated Dnmt1 lacking the DNA methylation catalytic domain. Molecular analysis revealed that expression of CCAAT/enhancer-binding protein alpha (C/ebpa) was upregulated, which correlated with hypomethylation of CpG islands in the regulation regions of cebpa gene in Dnmt1 deficient HSPCs. Overexpression of a transcriptional repressive SUMO-C/ebpa fusion protein could rescue hematological defects in the dnmt1 mutants. Finally, dnmt1 and cebpa double null embryos exhibited no obvious abnormal hematopoiesis indicated that the HSPC defects triggered by dnmt1 mutation were C/ebpa dependent. Dnmt1 is required for HSPC maintenance via cebpa regulation during definitive hematopoiesis in zebrafish.
    Journal of Hematology & Oncology 02/2015; 8(1). DOI:10.1186/s13045-015-0115-7 · 4.81 Impact Factor
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    ABSTRACT: Hematopoietic stem and progenitor cells (HSPCs) can reconstitute and sustain the entire blood system. We generated a highly specific transgenic reporter of HSPCs in zebrafish. This allowed us to perform high-resolution live imaging on endogenous HSPCs not currently possible in mammalian bone marrow. Using this system, we have uncovered distinct interactions between single HSPCs and their niche. When an HSPC arrives in the perivascular niche, a group of endothelial cells remodel to form a surrounding pocket. This structure appears conserved in mouse fetal liver. Correlative light and electron microscopy revealed that endothelial cells surround a single HSPC attached to a single mesenchymal stromal cell. Live imaging showed that mesenchymal stromal cells anchor HSPCs and orient their divisions. A chemical genetic screen found that the compound lycorine promotes HSPC-niche interactions during development and ultimately expands the stem cell pool into adulthood. Our studies provide evidence for dynamic niche interactions upon stem cell colonization. PAPERFLICK: Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell 01/2015; 160(1-2):241-252. DOI:10.1016/j.cell.2014.12.032 · 32.24 Impact Factor
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    ABSTRACT: Hematopoietic and vascular development share many common features, including cell surface markers and sites of origin. Recent lineage tracing studies have established that definitive hematopoietic stem and progenitor cells arise from VE-cadherin(+) hemogenic endothelial cells of the aorta-gonad-mesonephros (AGM) region, but the genetic programs underlying the specification of hemogenic endothelial cells remain poorly defined. Here, we discovered that Notch induction enhances hematopoietic potential and promotes the specification of hemogenic endothelium in differentiating cultures of mouse embryonic stem cells, and identified Foxc2 as a highly upregulated transcript in the hemogenic endothelial population. Studies in zebrafish and mouse embryos revealed that Foxc2 and its orthologs are required for the proper development of definitive hematopoiesis and function downstream of Notch signaling in the hemogenic endothelium. These data establish a pathway linking Notch signaling to Foxc2 in hemogenic endothelial cells to promote definitive hematopoiesis. Copyright © 2015 American Society of Hematology.
    Blood 01/2015; 125(9). DOI:10.1182/blood-2014-04-568170 · 10.45 Impact Factor

Publication Stats

32k Citations
4,686.37 Total Impact Points


  • 1996-2015
    • Howard Hughes Medical Institute
      Ашбърн, Virginia, United States
  • 1989-2015
    • Boston Children's Hospital
      • • Division of Genetics
      • • Manton Center of Orphan Disease Research
      • • Department of Pediatrics
      Boston, Massachusetts, United States
  • 1987-2015
    • Harvard University
      • • Department of Chemistry and Chemical Biology
      • • Department of Developmental Biology
      Cambridge, Massachusetts, United States
  • 1986-2015
    • Harvard Medical School
      • • Department of Surgery
      • • Department of Pathology
      • • Department of Pediatrics
      • • Department of Genetics
      • • Department of Medicine
      Boston, Massachusetts, United States
    • University of Massachusetts Boston
      Boston, Massachusetts, United States
  • 2014
    • Neural Stem Cell Institute
      Rensselaer, New York, United States
  • 1992-2014
    • Dana-Farber Cancer Institute
      • • Department of Pediatric Oncology
      • • Department of Medical Oncology
      Boston, Massachusetts, United States
    • Istituto Superiore di Sanità
      • Department of Haematology, Oncology and Molecular Medicine
      Roma, Latium, Italy
  • 2009
    • Beth Israel Deaconess Medical Center
      • Division of Hematology/Oncology
      Boston, MA, United States
  • 2008
    • University of Utah
      • Department of Pediatrics
      Salt Lake City, Utah, United States
  • 2007
    • University of Pittsburgh
      • Department of Medicine
      Pittsburgh, Pennsylvania, United States
  • 2005-2006
    • Brigham and Women's Hospital
      • Department of Pathology
      Boston, MA, United States
  • 2002
    • Salk Institute
      لا هویا, California, United States
  • 2001
    • National Human Genome Research Institute
      베서스다, Maryland, United States
  • 1999-2001
    • Princeton University
      • Department of Molecular Biology
      Princeton, New Jersey, United States
    • Washington University in St. Louis
      • Department of Genetics
      Saint Louis, MO, United States
    • University of Rochester
      • Department of Biology
      Rochester, NY, United States
  • 2000
    • Wolfson Childrens Hospital
      Jacksonville, Florida, United States
  • 1994
    • Massachusetts General Hospital
      • Diabetes Laboratory
      Boston, MA, United States