Annual Scientific Meeting
Information Exchange Abounds at 2011 Annual Scientific Meeting
There is still time to register for the Vancouver meeting to discuss the latest advances in the field of hematology and stem cell biology with the leading researchers in the field. Register now!
Time and again, ISEH Annual Scientific Meeting attendees point to its "smallness” as its biggest draw.
"I like that the Society is not too big, allowing members to interact easily with one another and form lifelong relationships,” said Hal Broxmeyer, the 2011 Donald Metcalf Award winner.
"At ISEH, you can approach people, have a beer and talk science with them,” explains Grover C. Bagby, Jr., MD, former ISEH president and current Publications Committee chair. "People truly want to interact with one another about science; it is not a place where people just schmooze with the ‘big guys' for political gain or spend all their time at committee meetings.”
A few meeting highlights follow.
Saturday, 27 August
16:00 – 17:45
ISEH President David Scadden, MD, Massachusetts General Hospital, has selected the topic "Metabolism in Normal and Malignant Hematopoiesis” for the 2011 Presidential Symposium. At Dr. Scadden's invitation, the session includes Celeste Simon, University of Pennsylvania; Toshio Suda, Keio University; and Eduardo Moreno, University of Bern. Their abstracts follow.
OXYGEN AVAILABILITY AND STEM/PROGENITOR CELL MATURATION
Celeste Simon, Howard Hughes Medical Institute/Abramson Family Cancer Research Institute Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
Stem and progenitor cells reside in specialized microenvironments that regulate their function. While some stem/progenitor cells are perivascular, others clearly occupy hypoxic niches and may be regulated by O2 gradients. We are currently evaluating underlying mechanisms for the impact of O2 levels on stem and progenitor cells within distinct microenvironments. We have
previously shown that neural stem cells within the adult hippocampus are closely associated with low O2 regions and that hypoxia‐inducible factor 1α (HIF‐1α), a principle mediator of hypoxic adaptations, modulates Wnt‐catenin signaling to maintain stem cell proliferation, differentiation, and neuronal maturation. We have extended these findings to other stem cell populations, such as those of adult muscle and bone marrow. Our findings will be presented at this meeting.
GLYCOLYTIC METABOLISM OF HEMATOPOIETIC STEM CELLS
Toshio Suda, Department of Cell Differentiation, Keio University, Keio, Japan
Hematopoietic stem cells (HSCs) are sustained in a specific microenvironment known as the stem cell niche. Adult HSCs are kept quiescent during the cell cycle in the endosteal niche of the bone marrow. Normal HSCs maintain intracellular hypoxia, stabilize the hypoxia‐inducible factor‐1α (HIF‐1α) protein and generate ATP by anaerobic metabolism. In HIF‐1α‐ deficiency, HSCs became metabolically aerobic, lost cell cycle quiescence, and finally exhausted. An increased dose of HIF‐1α protein in VHL mutated HSCs and their progenitors induced cell cycle quiescence and accumulation of HSCs in the BM (Takubo et al. Cell Stem Cell, 2010). Next, we have performed the metabolomic analysis in HSCs. Up‐regulation of pyruvate dehydrogenase kinases (PDKs) enhanced the glycolytic pathway, cell cycle quiescence and stem cell capacity. HSCs directly utilize the hypoxic microenvironment to maintain their slow cell cycle by HIF‐1∩üí‐dependent metabolism. Down‐regulation of mitochondrial metabolism might be reasonable in terms of reactive oxygen species (ROS) regulation, which induce stem cell differentiation.
THE GENETICS OF CELL COMPETITION
Eduardo Moreno, IZB, University of Bern, Bern, Germany
Multicellular animals have mechanisms that ensure that viable but suboptimal cells do not accumulate. How groups of cells compare their relative fitness levels and decide which cell will remain in the tissue (winner cell) and which cell will die (loser cell) is starting to become clear. Recent work in Drosophila has shown that the decision relays on the balance between two factors: Flower (Fwe) and dSPARC. dSPARC and Flower function in parallel pathways and have opposing roles. The eventual death of the loser cells depends on the balance of those two opposing signals. The study of the pathways that reveal cellular fitness may shed light in several fields such as the origins and evolution of animal multicellularity and is impacting our understanding of cancer, development, stem cell biology and ageing.
ISEH Donald Metcalf Lecture Award
Thursday, 25 August
15:15 – 16:30
Established in 1999 in honor of Professor Donald Metcalf, "the father of hematopoietic cytokines," for his pioneering work on the control of blood cell formation, the Donald Metcalf Award recognizes distinguished scientists in the field. The 2011 winner is Hal E. Broxmeyer, Ph.D., Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA. His presentation abstract follows.
A CAREER IN EXPERIMENTAL HEMATOLOGY AND STEM CELL RESEARCH: LESSONS FROM THE PAST, PRESENT FOCUS, AND FUTURE ENDEAVORS
The focus of my laboratory is, and has been for over 40 years, to understand hematopoietic stem and progenitor cell functions (self‐renewal, proliferation, survival, differentiation, migration, mobilization, and homing) and regulation of these processes through cytokine mediated intracellular signaling. The ultimate goal is to translate experimentally‐derived information for clinical benefit. The ride to the present has been at times exciting and frustrating, and sometimes both at the same time. This lecture will track my career, in short, through a number of stages from graduate school to the present with each one setting up possibilities for the next stage.
ISEH McCulloch and Till Lecture Award
Sunday, 28 August
8:00 – 9:00
Established in 2004 in honor of Professor Ernest McCulloch and Professor James Till, the McCulloch and Till Award recognizes junior scientists in the field of hematology and stem cells. The 2011 McCulloch and Till Award winner is Iannis Aifantis, Ph.D., associate professor of pathology, New York University School of Medicine, Early Career Scientist, Howard Hughes Medical Institute, New York, NY, USA. Dr. Aifantis' presentation is UBIQUITINATION AS A NOVEL LEVER OF REGULATION OF STEM CELL DIFFERENTIATION AND SELF-RENEWAL.
Seven young investigators speak on Saturday. See the Young Investigators section of this e-newsletter for details.
Engaging presentations featuring new research were selected during the late-breaking abstract submission period. Check your onsite program materials for abstracts and be sure to attend these sessions.
PYRUVATE KINASE M2 PLAYS DISTINCT ROLES IN HEMATOPOIETIC STEM CELLS AND LEUKEMIA
Y. Wang, W. Israelsen, M. Vander Heiden, D. Scadden
A WNT16-DELTAC/DELTAD SIGNALING AXIS SUGGESTS MURAL ENDOTHELIAL INTERACTIONS PRODUCE HEMOGENIC ENDOTHELIUM
W. K. Clements, A. D. Kim, K. G. Ong, D. Traver
TRACKING GATA2 EXPRESSION AND ITS ROLE DURING MOUSE HEMATOPOIETIC DEVELOPMENT
P. Kaimakis, E. de Pater, T. Yokomizo, R. van der Linden, E. Dzierzak
WNT5A DOES NOT INCREASE THE MAINTENANCE AND EXPANSION OF COMPETITIVE LONG-TERM REPOPULATING (LTR) HEMATOPOIETIC STEM CELLS (HSCS) WHEN CULTURED STROMA-FREE
A. Schaap-Oziemlak, S. Schouteden, C. Verfaillie
IN VIVO IMATINIB TREATMENT HAS NO EFFECT ON THE BIOLOGY OF MESENCHYMAL STEM CELLS (MSC) AFTER THEIR IN VITRO EXPANSION
E. Flores-Figueroa, K. P. Estrada-Gonzalez, L. Gomez-Ceja, J. Montesinos, N. Delgado, L. Meillon, E. Sanchez-Valle, H. Mayani, I. Valencia-Plata, A. M. Chavez-Gonzalez, M. Ayala-Sanchez, J. Vela-Ojeda
FETAL HEMATOPOIETIC STEM CELLS RESIDE ADJACENT TO NESTIN:GFP PERIVASCULAR NICHES
J. Ahmed, M. Merad, P. Frenette
IMPAIRMENT OF HEMATOPOIETIC STEM CELL (HSC) NICHES IN G-CSF MOBILIZED BONE MARROW RESULTS IN RAPID MOBILIZATION OF SERIALLY RECONSTITUTING HSC AND DEFECTS IN RECONSTITUTION POTENTIAL OF HSC REMAINING IN THE BONE MARROW
J. Levesque, V. Barbier, B. Nowlan, D. McCarthy, I. G. Winkler
AMG 319 IS A POTENT, SELECTIVE AND ORALLY BIOAVAILABLE PHOSPHATIDYLINOSITOL-3 KINASE DELTA (PI3KΔ) INHIBITOR THAT SUPPRESSES PI3K-MEDIATED SIGNALING IN AND VIABILITY OF NEOPLASTIC B CELLS
A. Sinclair, D. Metz, T. Cushing, L. Liu, R. Brake, C. Starnes, K. Henne, G. Means, I. Archibeque, B. Mattson, A. Drew, J. Pistillo, A. Al-Assaad, G. Molineux
INHIBITION OF THE INNATE IMMUNE COMPLEX AS A NOVEL THERAPEUTIC STRATEGY IN MYELOID MALIGNANCIES
D. Starczynowski, G. Rhyasen, L. Bolanos, J. Fang
A SIMPLE IMMUNOMAGNETIC, COLUMN-FREE METHOD FOR THE ENRICHMENT OF LYMPHOID PROGENITORS FROM MOUSE BONE MARROW
N. Tabatabaei-Zavareh, T. E. Thomas, M. A. Fairhurst
A POPULATION FEATURING MORPHOLOGICAL AND MOLECULAR CHARACTERISTICS OF VERY SMALL EMBRYONIC LIKE STEM CELLS (VSELS) IS PRESENT IN NORMAL HUMAN PERIPHERAL BLOOD OF ADULTS
H. Sovalat, A. Eidenschenk, M. Scrofani, P. Hénon
ASYMMETRIC CELL DIVISION OF HEMATOPOIETIC STEM CELLS
D. Loeffler, T. Schroeder
SELECTIVE SMALL MOLECULE INHIBITION OF P110Α AND Δ ISOFORMS OF PI-3 KINASE WITH IS CYTOTOXIC TO HUMAN AML PROGENITORS
Y. Xing, B. Gerhard, D. E. Hogge
SHEAR STRESS REGULATES ADHESION AND ROLLING OF HEMATOPOIETIC AND LEUKEMIC STEM CELLS EXPRESSING CD44
I. Taubert, C. E. Christophis, M. Hanke, A. Rosenhahn, M. E. Grunze, A. D. Ho
INVESTIGATING THE MYELOID PROGENITOR NICHE IN NORMAL HEMATOPOIESIS AND MYELOPROLIFERATIVE NEOPLASM
M. Binnewies, E. Passegue
MAINTAINING HUMAN HEMATOPOIETIC STEM CELLS IN MICE
C. Waskow, N. Cosgun
LENTIVIRAL TRANSFER MEDIATED RNA INTERFERENCE CAN DOWNMODULATE EXPRESSION OF ABO, RHD AND KIDD BLOOD GROUP ANTIGENS IN THE ERYTHROID PROGENY OF TRANSDUCED CORD BLOOD CD34+ CELL POPULATIONS
C. Bagnis, S. Chapel, J. Chiaroni, P. Bailly
ROLE OF HYPOXIA-INDUCIBLE FACTORS IN ACUTE PROMYELOCYTIC LEUKEMIA
N. Coltella, R. Cuttano, J. Guarnerio, S. Cavalli, M. Ponzoni, R. Bernardi
DIFFERENTIATION OF BONE MARROW MESENCHYMAL STEM CELLS INTO INSULIN PRODUCING CELLS IN COMPARISION WITH UMBILICAL CORD MESENCHYMAL STEM CELLS IN CO-CULTURE WITH PANCREATIC STROMAL CELLS
R. Khoshchehreh, M. Ebrahimi, H. Baharvand, M. Bagheban Islami Nejad, F. Samani
NOVEL ANTI-LYMPHOMA FUNCTION OF SCUTELLARIN
Q. Zhou, S. Zhang, Y. Feng, Z. Cao, J. Tu, Y. Pan, B. Shang, R. Liu, M. Bao, P. Gu
A FLOW CYTOMETRY BASED MITOXANTRONE EFFLUX ASSAY FOR PREDICTING CHEMOTHERAPY REFRACTORINESS IN NEWLY-DIAGNOSED ACUTE MYELOID LEUKEMIA (AML)
H. Kim, L. Bernard, J. Berkowitz, J. Nitta, D. E. Hogge
HETEROGENEITY IN TEMPORALLY-DEFINED QUIESCENT HEMATOPOIETIC STEM CELLS
K. Moore, J. Qiu, D. Papatsenko
SCL IS REQUIRED FOR C-KIT-DEPENDENT HEMATOPOIETIC PROGENITOR CELL SURVIVAL
T. Hoang, J. Lacombe, G. Krosl, M. Tremblay, R. Martin, S. Herblot, P. Aplan
GENETIC AND FUNCTIONAL ANALYSIS OF A PANEL OF HUMAN MONOCLONAL ANTIBODIES AGAINST GM-CSF CLONED FROM IDIOPATHIC PULMONARY ALVEOLAR PROTEINOSIS (IPAP) PATIENTS
ENHANCED PROLIFERATION OF MULTIPOTENT HUMAN ADIPOSE TISSUE DERIVED MESENCHYMAL PROGENITOR CELLS CULTURED IN A NOVEL XENO-FREE MEDIUM
B. J. Short, T. E. Thomas, A. C. Eaves, B. Wognum, R. Wagey
CD34+CD38-CD45RA-CD90+CD49F+RHO- CORD BLOOD CELLS CONTAIN THE SAME FREQUENCY OF CELLS WITH 12-WEEK LYMPHO-MYELOID OUTPUTS ON ENGINEERED STROMA AS IN NSG MICE FOR 20 WEEKS
M. Liu, A. Cheung, S. Imren, K. Lucke, D. E. Hogge, C. Eaves
MENIN-MLL PATHWAYS IN HEMATOPOIESIS
P. Ernst, T. Gan, E. L. Artinger, K. Zaffuto, M. Myerson, T. Rabbitts, B. Li, B. Mishra
IDENTIFICATION OF THE HIERARCHY OF HEMATOENDOTHELIAL PROGENITORS IN HESC DIFFERENTIATION CULTURES
K. Choi, M. Vodyanik, P. Togarrati, K. Suknuntha, Smarjeet, R. Stewart, M. Probasco, J. Thomson, I. Slukvin
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Take a quick tour of the July and August issues and get a feel for the great scientific content. Read the full issues.
In this Issue – July 2011
Plerixafor (AMD3100) in hematologic malignancies: mobilizing hematopoietic stem cells for some patients and leukemia stem cells for others
Uchida et al and Mohty et al
Plerixafor is a bicyclam molecule that antagonizes the binding of SDF-1 to its receptor CXCR4, and is becoming more widely used for the mobilization of hematopoietic stem (HSCs) and progenitor cells in combination with G-CSF for patients with lymphoma and multiple myeloma. Clinical trials have shown that a combination of G-CSF and plerixafor mobilizes a higher number of CD34+ cells than G-CSF alone and these cells have a more primitive phenotype. In the study by Uchida et al, they compared two mobilization protocols, G-CSF+SCF vs G-CSF+ Plerixafor in rhesus monkeys and showed that the latter resulted in mobilization of 2-fold more CD34+ cells, capable of long term multilineage reconstitution and transgene expression in vivo. These monkeys also showed accelerated lymphocyte recovery after transplantation probably due to increased numbers of lymphoid progenitors within the mobilized CD34+ cells. Similarly in one clinical trial using G-CSF+ Plerixafor an effective mobilization of lymphocyte progenitors was shown in patients that displayed rapid lymphocyte recovery resulting in a lower risk of relapse in these patients with lymphoma. Faster immune reconstitution could also have a dramatic impact on preventing infections post transplant therefore improve significantly transplant associated morbidity and mortality. Mohty et al elegantly review the role of Plerixofar and other CXCR4 antagonists in the treatment of hematologic malignancies that include mobilization of HSCs for transplantation in some settings and mobilization of leukemia stem cells (LSCs) to the peripheral blood and sensitizing them to chemotherapy to improve clinical outcomes in others. The use of Plerixafor in future clinical trials will probably expand due to its superior mobilization of primitive HSCs and lymphoid progenitors, as well as its unique mobilizing potential of LSCs.
Progress towards chemotherapeutic agents or formulations with selective toxicity for leukemic cells
Kim et al
CPX-351 is a novel liposomal formulation of cytarabine and daunorubicin. Clinical trials have shown that it is well tolerated and capable of inducing CR in some refractory and relapsed AML patients. The enhanced antileukemic efficacy of CPX-351 has been shown in mouse models using leukemia cell lines. In this study, Kim et al tested the efficacy and toxicity of CPX-351 for the first time on candidate leukemic stem and progenitor cells from AML patients with chemosensitive and refractory disease and compared it to standard delivery of free drugs. They showed that CPX-351was selectively cytotoxic for AML CFCs, and spared normal progenitors from mobilized PB and BM. Interestingly CPX-351 and free drugs had similar potency. This exciting finding warrants further studies in which the toxicity of this compound is tested on NOD-SCID repopulating normal hematopoietic and leukemia stem cells. Patients with high risk AML, which also include older patients, could benefit from such formulations whereby reduced toxicity to normal hematopoiesis but efficacy on leukemic cells would reduce periods of myelosuppression in these patients.
PAX5, the guardian of B cell identity
Ingram et al
The transcription factor PAX5 plays an important role in controlling B-cell identity by activating B-cell specific genes and silencing genes of other lineages. Several PAX5 translocations with different partner genes (PAX5-ETV6, PAX5-FOXP1, PAX5-EVI3 and PAX5-ELN) have been identified in B-cell malignancies. In this study, Ingram et al investigated further how PAX5 regulated the silencing of the myeloid-specific colony-stimulating-factor-receptor (Csf1R) gene in B cells. They demonstrated that PAX5 on the one hand repressed mRNA transcription by reducing the frequency of binding of the basal transcription machinery to the Csf1r promoter and on the other hand, activated antisense RNA expression. Dissecting mechanisms involved in the tight control of the level, pattern and function of PAX5 expression will be useful to enhance our understanding of normal and malignant lymphopoiesis and help to develop novel therapeutics for B-cell malignancies.
In this Issue – August 2011
A minibody for human Mpl: efficient stimulant of human megakaryopoiesis
Matsuki et al
Megakaryopoiesis and platelet production depend on Thrombopoietin (TPO) binding to its receptor c-MPL on hematopoietic progenitor cells. Since its discovery in 1994, TPO has sparked tremendous hope that it would help reduce the need for platelet transfusions for many patients suffering from acute and chronic thrombocytopenia. Clinical trials using either the recombinant human TPO or pegylated recombinant human megakaryocyte growth and development factor (a truncated molecule of TPO) have been disappointing, as neither proved to be useful for patients with severe thrombocytopenia, and resulted in the development of autoantibodies. Thus, there is an urgent need for a nonimmunogenic, efficient and safe thrombopoietic growth factor that could dramatically reduce the morbidity for patients with severe thrombocytopenia. One such agent is Eltrombopag, a small molecule agonist of c-MPL, currently available as a pill for clinical use. Another promising TPO analogue is a humanized VB22B sc(Fv)2 minibody (huVB22B), an antibody against c-MPL that has been shown to increase the platelet number in cynomologus monkeys. In this study, Matsuki et al show that huVB22B is as potent as thrombopoietin and eltrombopag in stimulating megakaryocte generation from human CD34+ cells in vitro, it is most efficient in increasing the number of proplatelet forming megakaryocytes, and similar to Eltrombopag, does not enhance platelet aggregation. The data suggest that huVB22B minibody is a promising agent for clinical use.
Bcl-2: a better therapeutic target than c-Myc?
Sasaki et al.
Patients with diffuse large B-cell lymphoma (DLBCL) with concomitant overexpression of Bcl-2 and c-Myc respond poorly to chemotherapy and have an unfavorable prognosis. In order to develop effective treatment strategies for these patients, it is crucial to identify the mechanism of chemoresistance in such lymphomas. In this study, Sasaki et al demonstrate that targeting Bcl-2 alone in the cell lines derived de novo from two chemoresistant patients, was more effective than c-Myc alone for enhancing the cell killing by chemotherapeutic agents commonly used in the treatment of these lymphomas. However, simultaneous inhibition of both Bcl-2 and c-Myc was most effective in overcoming chemoresistance and raises this strategy as a future treatment approach. While clinically useful c-Myc inhibitors are not in hand, Navitoclax, a Bcl-2 inhibitor, is currently being tested in clinical trials, which suggests that such an agent could potentially be incorporated into the standard chemotherapy regimens for patients with DLBCL with concurrent Bcl-2 and c-Myc overexpression.
Novel positive regulators of human pluripotent stem cells: Retinoblastoma (RB)-binding proteins 4 and 9
O'Connor et al
Human pluripotent stem (PS) cells have great potential in the field of regenerative medicine for treatment of a wide array of diseases. Significant progress has made in this field of research, but better understanding the genes involved in human PS cell maintenance will further improve their generation, expansion and differentiation. In this study, O'Connor et al identified two new candidate regulators of pluripotency, RB-binding protein 4 (RBBP4) and 9 (RBBP9), and present evidence that both genes are required for maintaining the pluripotent state of human EC, ES and iPS cells. The specificity of this finding was confirmed by showing a concomitant decrease in expression of pluripotency genes, POU5F1, NANOG, SOX2, and FOXD3, and increase in expression of genes involved in organogenesis upon reduction of RBBP4 or RBBP9 levels. The loss of RBBPs also resulted in a significant decrease in the frequency of CFCs able to form alkaline phosphatase-positive colonies, consistent with loss of pluripotency. Future studies should help determine the molecular mechanisms involved in the role of RBBP4 and RBBP9 in the maintainance of pluripotency and whether they play a role in somatic cell reprogramming.
The publishing team seeks manuscripts describing research involving in vivo and ex vivo studies in the following areas: cell cycle regulation, cytokines, erythropoiesis, gene therapy, general hematopoiesis, granulopoiesis, hematological malignancies, immunobiology, immunotherapy, lymphopoiesis, megakaryocytopoiesis, microenvironment, monocyte development, molecular genetics, signal transduction, stem cell biology, and experimental as well as clinical stem cell transplantation.
Visit the Experimental Hematology website for more information.
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Young Investigators Committee Launches Career Resources
There is now one more reason for young investigators to join ISEH – the new Career Resource section at www.iseh.org. Here you will find loads of material on finding and applying for grants. Young investigators who have traveled this trail – and knew there should be an easier way – have compiled this helpful information for the good of others!
The page includes a wealth of links to external sites for assistance, including a site with examples of funded applications.
"We are all scattered geographically which makes it a challenge for networking outside your institution,” says Marie-Dominique Filippi, Cincinnati Children's Hospital Research Foundation and member of the Young Investigators Committee. "I recently got my first grant, and it was most certainly a trial!”
Filippi had good support at the foundation and learned so much in the process that she combined with fellow committee member Teresa Bowman, Children's Hospital Boston, to share their lessons with other ISEH members.
"We don't always get great direction regarding applying for grants,” Bowman adds. "When I first started as a post doc, I had to figure out what I could apply for, what the timelines were, etc. One person cannot possibly know all the grant opportunities; we wanted to open people's eyes.”
The ISEH page also includes a list of frequent mistakes such as lack of acknowledging controversies, as well as unfocused aims and unclear goals and unclear interpretation and implications of the data.
You Can Help!
The career resource page is there and ready for you to take what you need. But, we ask that you also return the favor by sharing your experiences on the interactive blog. Get started now!
Seven Selected to Present Work in Vancouver
Making a technical presentation at your Society's annual meeting is a huge step in a young investigator's career. Four Ph.D. students and three post-docs will take the podium in Vancouver to do just that Saturday, 27 August, 13:45 – 15:45.
"It is a great pleasure to present my results to renowned scientists and colleagues, get their feedback and be an active part of this scientific community,” states Alessandro Di Tullio. Ph.D. student, Center for Genomic Regulation, Spain.
See below for information on the young investigator presentations.
THE TRANSCRIPTION FACTOR MEIS1 MARKS A MEGAKARYOCYTE‐SPECIFIC ALTERNATIVE PROMOTER OF THE DNM3 LOCUS AT THE POSITION OF A GWAS SEQUENCE VARIANT FOR PLATELET VOLUME
Sylvia Nürnberg, Peter A. Smethurst, Rafik Rizkallah, Nicole Soranzo, Augusto Rendon, Willem H. Ouwehand
We have recently identified 12 quantitative trait loci for the volume (MPV) and three for the count of platelets by a Genome‐Wide Association Study (GWAS). One of the 12 association single nucleotide polymorphisms (SNPs), rs10914144, lies in intron 2 of the DNM3 gene on chromosome 1q24.3. DNM3 encodes the 97 kDa Dynamin (DNM) 3 protein that is part of the DNM superfamily of GTPases, which are involved in the formation of cytoplasmic vesicles by pinching off tubules from the parental membrane2. In mature human blood cells the DNM3 gene is strongly transcribed only in megakaryocytes (MK)3, while other expression studies indicate that the transcript is also present in brain, as well as lung and testis. In this study we set out to elucidate the mechanism by which sequence variation in the DNM3 locus exerts its effect on platelet volume.
"By participating in the ISEH meeting, I hope to gain a deeper insight into the most recent developments within the field and some inspiration to the challenges that lie ahead."
Sylvia Nürnberg, 4th year Ph.D. student, University of Cambridge, UK
TRANSDIFFERENTIATION OF BURKITT'S LYMPHOMA CELLS INTO QUIESCENT MACROPHAGES AND INHIBITION OF LEUKEMOGENICITY
F. Rapino, E. Robles, J. Larrea, J. Martinez Climent, T. Graf
Direct reprogramming of differentiated cells by transcription factors has yielded new insights into the mechanisms of cell fate specification. In previous work we have shown that mature murine B cells can be converted into macrophages by overexpression of C/EBPα, but whether human cells can be transdifferentiated was not known. We have now developed a human transdifferentiation system using a Burkitt's Lymphoma (BL) cell line called Seraphina in which we have stably expressed C/EBPαER‐GFP. The inducible derivative, called BLaER, can be converted into macrophages upon induction of C/EBPα with b‐estradiol. Essentially 100% of the cells upregulate the myeloid marker Mac‐1 and downregulate the B cell marker CD19 within 5 days. They show dramatic changes in morphology, become attached and increase in size and granularity yet retain immunoglobulin rearrangements characteristic of the original B cell line.
"It's a great pleasure and honor for me to present my work during the Young Investigator Award Session. As sharing results with other investigators is fundamental in science, this gives me the chance to get feedback and suggestions on my work.”
Francesca Rapino, Ph.D. student, Center for Genomic Regulation, Spain
C/EBPα INDUCED TRANSDIFFERENTIATION OF PRE-B CELLS INTO MACROPHAGES INVOLVES NO OVERT RETRODIFFERENTIATION
Alessandro Di Tullio, Thien Phong Vu Manh, Alexis Schubert, Robert Månsson and Thomas Graf
An increasing number of transcription factor mediated lineage conversions have been described in recent years. Although most of these concern cells belonging to the same germ layer, such as within the mesoderm (Ieda et al., 2010) or within the ectoderm (Zhou et al., 2008), recently a ‘long jump' between mesoderm and ectoderm has also been reported (Vierbuchen et al., 2010). It has been suggested that lineage conversions represent direct transitions from one differentiated state into another, with cells 'hopping over the mountains' of Waddington's epigenetic landscape (Zhou and Melton, 2008; Graf and Enver, 2009). Indeed, no reactivation of transcription factors characteristic of progenitors could be observed during the conversion of endocrine into exocrine cells and of fibroblasts into cardiomyocytes (Zhou et al., 2008; Ieda et al., 2010). However, these studies did not define precursors as a combination of markers and did not rule out the possibility that during transdifferentiation the expression of selected progenitor restricted genes is transiently reactivated at the mRNA level.
"My main goal as I move forward in my career will be trying to do high level research and find grants that will allow me to be competitive in the scientific field, keeping an eye on the fact that science first is a passion and then is work.”
Alessandro Di Tullio. Ph.D. Student, Center for Genomic Regulation, Spain
TROPHOBLASTS REGULATE THE PLACENTAL HEMATOPOIETIC NICHE THROUGH PDGF‐B SIGNALING
A. Chhabra, A. J. Lechner, A. Acharya, M. Ueno, B. Van Handel, L. Iruela‐Arispe, M. Tallquist, H. Mikkola
The goals of hematopoiesis during embryogenesis are two‐fold, to rapidly produce red blood cells to support the survival and development of the embryo, and to establish a pool of undifferentiated hematopoietic stem cells (HSC) for postnatal life. These goals are achieved by segregation of fetal hematopoiesis into multiple waves that are executed in distinct anatomical sites and microenvironmental niches. However, the microenvironmental cues that promote "stemness” vs. differentiation in the different fetal hematopoietic sites remain poorly understood. The placenta is a recently discovered hematopoietic organ that supports HSC generation and expansion without promoting their differentiation. The placental HSC pool is thought to reside in the placental labyrinth, which is comprised of an intricate vascular network surrounded by trophoblasts. Our data reveals that PDGF‐B signaling in trophoblasts is an essential component of the unique hematopoietic microenvironment of the placenta that protects hematopoietic stem and progenitor cells (HSPCs) from premature differentiation.
CONVERSION OF PROSPECTIVE HEMOGENIC ENDOTHELIUM TO CARDIOGENIC FATE IN THE ABSENCE OF SCL/TAL1
A. Montel‐Hagen, B. Van Handel, R. Ferrari, R. Sasidharan, H. Nakano, T. Org, J. Zhou, X. Li, M. Pellegrini, S. H. Orkin, A. Nakano, S. K. Kurdistani, H. K. Mikkola
Hematopoietic stem and progenitor cells originate from hemogenic endothelial precursors in the major blood vessels in the embryo and extraembryonic tissues. However, it is not known how this unique endothelium is specified. Here we show that the establishment of the hematopoietic transcriptional program in endothelium is driven by the bHLH transcription factor Scl/tal1. Surprisingly, lack of Scl induced fate switching of endothelium in hemogenic tissues to the cardiac lineage. Scl deficient embryos displayed a dramatic upregulation of cardiac transcription factors and structural proteins within the endothelial cells in the yolk sac, which is the first hematopoietic organ in the embryo. Furthermore, yolk sac vasculature in the mutant embryos contained cells co‐expressing both endothelial and cardiomyocyte specific proteins. Strikingly, lack of Scl resulted in the generation of spontaneously beating cardiomyocytes in the yolk sac.
"Participating in the ISEH meeting is an excellent opportunity to meet scientists that we know only from their publications. It is so exciting to have the possibility to discuss science directly with them. It is a great way to build networking contacts for future collaborations.”
Amélie Montel-Hagen, Ph.D., post doc, UCLA, Los Angeles, USA
BMP AND WNT PATHWAY REGULATION OF LINEAGE‐SPECIFIC GENE PROGRAMS UNDERLIE HEMATOPOIETIC REGENERATION
T. V. Bowman, E. Trompouki, L. N. Lawton, Z. Fan, D. Wu, A. DiBiase, C. S. Martin, J. N. Cech, A. K. Sessa, J. L. Leblanc, P. Li, G. C. Heffner, G. Q. Daley, R. F. Paulson, R. A. Young, L. I. Zon
BMP and Wnt signaling pathways play various roles in hematopoiesis ultimately through transcriptional regulation via SMAD and TCF transcription factors respectively. To define potential target genes of these pathways in hematopoietic cells, we performed chromatin immunoprecipitation coupled with sequencing (ChIP‐seq) for SMAD1 and TCF7L2. Comparison of these results with ChIP‐Seq of GATA1/2 in K562 cells and C/EBPα in U937 cells showed that more than 70% of TCF7L2 and SMAD1 targets co‐localize with these cell‐specific factors at well‐known lineage‐specific genes. During in vitro differentiation of human hematopoietic mobilized peripheral blood CD34+ progenitor cells, the binding sites shifted from genes from all hematopoietic lineages to erythroid specific genes. A similar reallocation of binding sites was observed during differentiation of G1ER Gata1‐null cells by induced Gata1 expression, implying cell type specific transcription factors may direct the binding sites of the signaling factors.
"The questions of science have remained the same, but the speed and quantity of data we can produce is astronomical. A major challenge to all scientists in the ‘omics' era is to make sense of the data storms, while continuing to stay focused on addressing fundamentally important questions.”
Teresa Venezia Bowman, Ph.D., Research Fellow, Stem Cell Program, Children's Hospital Boston
CLONAL STABILITY OF MURINE HEMATOPOIETIC STEM CELLS IN VIVO
R. Lu, A. Czechowicz, J. Seita, I. L. Weissman
Hematopoietic stem cells (HSCs) comprise a critical reservoir for maintaining blood and immune system homeostasis. Yet it remains unclear how HSCs are recruited for differentiation. The ‘clonal succession model' proposes that small subsets of HSCs sequentially commit to differentiation. In contrast, the ‘clonal stability model' suggests that a single static group of HSCs continuously replenish the blood supply throughout an organism's lifetime. To discriminate between these two models, we have developed a novel experimental system to track single HSC differentiation in vivo. Our experimental system combines viral cellular barcoding with high‐throughput sequencing to simultaneously track hundreds of cells with single cell resolution and sensitivity. We used a lentiviral vector to insert unique 33‐mer DNA codes into HSCs' genomes to serve as genetic barcodes. ‘Barcoded' HSCs were transplanted into mice without any preconditioning regimens such as irradiation so as to mimic natural physiological conditions.
"The principal challenge for young investigators is to establish a solid reputation in the field. This not only requires us to produce strong bodies of work, but also requires us to widely convey our ideas to the field. The ISEH meeting provides a great opportunity to do this.”
Rong Lu, Ph.D., postdoctoral scholar at Stanford University
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ISEH Leadership Elected
Congratulations to the newly elected 2011-2012 ISEH Board of Directors! Your peers have expressed confidence in your ability to lead the Society.
Also, thank you to outgoing board members Toshio Suda, Mitchell Cairo, Susie Nilsson and Hanna Mikkola. We appreciate your service to the Society.
Margaret ("Peggy”) Goodell is a professor and director of the Stem Cells and Regenerative Medicine Center at Baylor College of Medicine, in Houston, Texas. Goodell received her doctorate from Cambridge University in England and underwent post-doctoral training at MIT and Harvard Medical School. At MIT, she developed the "side population” or "SP” method, commonly used for enrichment of hematopoietic stem cells. Her current research is focused on the fundamental mechanisms that regulate normal hematopoietic stem cells. Recent work has focused particularly on how interferon gamma and infectious stress stimulates stem cells, as well as epigenetic mechanisms of their regulation.
Marella de Brujin
Marella de Bruijn is currently a tenured group leader in the MRC Molecular Haematology Unit (MHU), Weatherall Institute of Molecular Medicine at the University of Oxford, and an associate of the Oxford Stem Cell Institute. Her research interest is in understanding the cellular processes and regulatory mechanisms that give rise to hematopoietic stem cells (HSCs) during embryogenesis. In particular, she studies the transcriptional regulation and role of the Runx1/AML1 transcription factor in the generation of blood cells from hemogenic endothelium, with the aim to expand our understanding of the transcriptional network that underlies de novo HSC generation. Her work is relevant to future studies aimed at generating HSCs in the clinic, and could provide a framework to explore the changes in the network associated with RUNX1/AML1 leukemia.
Bertie Göttgens is a reader in molecular haematology on a permanent position within the Department of Haematology, University of Cambridge. He runs an 11-strong research group funded through grants won competitively from a variety of funding agencies. The group is based in the Cambridge Institute for Medical Research, a multi-disciplinary centre of excellence within the Medical School of Cambridge University. The long-term research goal of the Göttgens group is to decipher the molecular hierarchy of transcriptional networks responsible for blood stem cell development. To this end, the group uses complementary state-of-the-art approaches including transgenic mice, bioinformatics, ChIP-Seq assays and mathematical modelling of stem cell regulatory networks.
James Palis is professor of pediatrics, oncology and biomedical genetics, and director of pediatric biomedical research at the University of Rochester Medical Center. He received his undergraduate and medical education at the University of Rochester. Following pediatric residency and hematology/oncology fellowship, he has cared for children with hematologic and oncologic disorders for more than 20 years. He has had a longstanding laboratory research program investigating the initial emergence and development of the hematopoietic system in the mammalian embryo. Palis has been a member of ISEH for more than 15 years, serving on the Publications Committee and is currently on the editorial board of Experimental Hematology.
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2011-2012 ISEH Board of Directors
President: Gerald De Haan, PhD (Holland)
President-Elect: Elaine Dzierzak, PhD (Netherlands)
Vice President: Peggy Goodell, PhD (USA)
Treasurer: Tao Cheng, MD (China)
Immediate Past President: David Scadden, MD (USA)
Marella de Brujin, PhD (UK)
Bertie Gottgens, PhD (UK)
Toshio Kitamura, MD, PhD (Japan)
James Palis, MD (USA)
Emmanuelle Passegué, PhD (USA)
Louise Purton, PhD (Australia)
Timm Schroeder, PhD (Germany)
David Traver, PhD (USA)
R. Keith Humphries, MD, PhD (Canada)
Editor-in-Chief Experimental Hematology
ISEH, comprised of industry leaders in hematology, immunology, stem cell research, and cell and gene therapy, connects members worldwide for the opportunity to advance scientific knowledge. Each issue of Connections in Hematology & Stem Cells will introduce you to those members. This issue, meet Stephen M. Sykes, Ph.D.
First Fellowship Winner Grateful for the Opportunity
Stephen M. Sykes Ph.D.
Massachusetts General Hospital, Center for Regenerative Medicine
Harvard Stem Cell Institute, Department of Stem Cell and Regenerative Biology, Harvard University
Boston, MA, USA
Stephen M. Sykes, Ph.D., said it was "definitely glorious” to receive notification that he had been named the first recipient of the ISEH Eugene Goldwasser Fellowship, supported by Amgen. Sykes is a postdoctoral fellow in the Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA.
The ISEH Eugene Goldwasser Fellowship, supported by Amgen, will be given annually to support the research activities of a deserving young investigator in the hematology field. Support will be a one-year, non-renewable $50,000 grant payable to the successful applicant's institution, for use as salary and/or other research support. The research may be basic or translational with a focus on experimental hematology, hematologic malignancies, hematopiesis or stem cell biology as it relates to hematology.
"This means a great deal to me,” Sykes exclaims. "It is a real honor to be chosen among what I can only assume were great candidates. Dr. Goldwasser's contributions to science are immeasurable, and I will definitely always look up to him. He did so much to translate work in the lab to the patient bedside. On a practical level, this fellowship provides me with protected time to carry out follow-up experiments on my current work.”
Sykes didn't start out to be a Ph.D. but as he moved along in his educational career, science found him.
"I grew up in Canada playing baseball,” he explains. "Well, the chances of playing professional baseball are relatively limited there. I received an opportunity to play baseball at a junior college in upstate New York. When I left, I promised my mother that I would put effort forth in my studies as well. Somewhere in those first two years, I realized that while I was a mediocre baseball player, I loved science and loved learning.”
His next stop on the education trail was a B.S. degree in biochemistry from Mount Allison University.
"At Mount Allison, my desire to pursue a career in biomedical sciences was strengthened by intense theoretical and practical coursework focused on the principles of molecular biology, metabolism and protein biochemistry,” he adds. "After graduation, I wanted to gain technical experience as well as perform research directed more towards cancer biology.”
Therefore, Sykes took a position in the laboratory of Dr. Xianxin Hua at the University of Pennsylvania.
"After the first six to eight weeks, I knew this was what I was meant to do,” Sykes concludes.
Two years later, he entered U Penn as a Ph.D. candidate and achieved his doctorate in cell and molecular biology in 2007. His first post-doc position took him to Dr. Gary Gilliland's lab at Brigham and Women's Hospital in Boston to study the role of the FOXO family of transcription factors in the maintenance of acute myeloid leukemia. When Dr. Gilliland left for industry, Sykes moved to David Scadden's laboratory at the Center of Regenerative Medicine at Massachusetts General Hospital and the Department of Stem Cell and Regenerative Biology at the Harvard Stem Cell Institute (Harvard University) and, with Dr. Scadden's encouragement, continued his work on FOXOs.
In Vancouver, Sykes will share his work that identifies a paradoxical role of the FOXO family of transcription factors supporting leukemia-initiating cell function in a multitude of genetically diverse acute myeloid leukemias.
"I attended the meeting in Melbourne last year and found it to be an intimate and interactive meeting,” he says. "I think ISEH is the right place for me, and I didn't need any encouragement to attend again in Vancouver. I really like the people I met at ISEH and the way they think about science.”
Sykes hopes that as he continues his work, it will become clearer to him how his research in the lab carries over to the clinic.
"The biggest challenge for me is to understand how basic research translates to patients,” he offers. "As a Ph.D., we have no patient contact and we can't set up clinical trials. We are still learning how our work moves forward to an effective drug. Maybe I can help find a way to work together with clinicians and industry to maximize everybody's knowledge.”
When asked what he likes to do outside of science, Sykes chuckled and said, "everybody in our field is constantly thinking about science.” However he indicates that the focus of his life outside of science is finding the energy to keep up with his three-year-old son.
"Man, that kid wears me out!”
ISEH members: Connect with Stephen through the ISEH member database. Click here to learn more about him or to build your personal profile.
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