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August 2012 Connections Newsletter
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Connections in Hematology & Stem Cells is supported in part by a grant from

In the August 2012 Issue

Annual Scientific Meeting
It's not too late to register
Book your travel arrangements today
Program highlight: Genetic and epigenetic mechanisms underlie hematopoietic stem cell aging
Program highlight: Donald Metcalf Lecture
ISEH would like to thank the sponsors and exhibitors of the ISEH 41st Annual Scientific Meeting

Society and Profession News
ISEH announces board of directors election results
Transcription Factor Lyl-1 Critical in Producing Early T-Cell Progenitors
Stem Cell Sector Validating Itself With Exciting First Half 2012
Stem Cell Opponents? Give Me Your Best Shot

Member Profile
Patricia Ernst Supports ISEH, New Investigators

Experimental Hematology
Explore key manuscripts in the August and September issues

Annual Scientific Meeting

ISEH 41st Annual Scientific Meeting
23-26 August 2012
Hotel Okura
Amsterdam, The Netherlands

ISEH's 41st Annual Scientific Meeting is just a few days away. The educational opportunities are extremely relevant to investigators' general and specific needs. The networking events are organized to be highly interactive and enjoyable. Travel and hotel arrangements are cost effective and accessible regardless of your starting point. ISEH and the volunteers responsible for coordinating the annual scientific meeting are extremely excited to see you onsite. For detailed information, please use the links below.

Online highlights:

It's not too late to register

There is still time to register and make travel arrangements to attend the ISEH 41st Annual Scientific Meeting, which is 23-26 August 2012 at the Hotel Okura in Amsterdam. The annual forum is a must-attend event focused on the exchange and discussion of original, unpublished and significant research advances in the areas of hematology and stem cell biology. This exclusive scientific meeting features leaders in the field as well as promising young scientists.

Unique with its intimate format, the scientific meeting includes more than 30 educational sessions, featuring lectures by our distinguished panel. The New Investigators track provides those entering the field the opportunity to meet and connect with highly regarded ISEH scientists. Online registration is now closed but you can register onsite at the meeting. 


Book your travel arrangements today

All events during the ISEH 41st Annual Scientific Meeting will be held at the conveniently located Hotel Okura Amsterdam – perfect for accommodating the compact scientific program schedule and maximizing networking time. The Hotel Okura Amsterdam is a five-star, luxury hotel located on the banks of the Amstel Canal, close to the financial, cultural, and entertainment districts of Amsterdam. Make your travel arrangements to arrive for meeting opening at 15:00 on Thursday 23 August. The meeting closes Sunday 26 August. Room reservations can only be made online; please click here. To receive the ISEH meeting hotel rate, please enter "Group Code" - ISEH2012.

Program highlight: Genetic and epigenetic mechanisms underlie hematopoietic stem cell aging
By I. Beerman, C. Bock, A. Meissner and D.J Rossi
Stem Cell and Regenerative Biology, Harvard University, Boston, Mass.

Within the blood system, the aging of the hematopoietic stem cell (HSC) compartment contributes to age-associated hematological pathophysiologies, including decreased regenerative potential, reduced immune competence and myelogenous disease predisposition. The mechanistic basis for age-related HSC decline is complex with evidence indicating the involvement of age-associated HSC clonal dominance, deregulation of lineage specification transcriptional programs and DNA damage accumulation. In this study, the presenters will provide evidence that both epigenetic and genetic mechanisms contribute to HSC aging.

Program highlight: Donald Metcalf Lecture
Transcriptional control of blood cell lineage and developmental stage

By S.H. Orkin
Department of Pediatric Oncology, Harvard Medical School, Boston, Mass.

Hematopoiesis has long served as a paradigm for transcriptional control and lineage specification. Hematopoietic stem cells (HSCs) generate the various mature blood cell types through diverse progenitor populations, characterized by surface marker and transcription factor profiles. Studies of hematopoietic-restricted transcription factors, coupled with conventional and conditional gene knockouts in the mouses, have provided insights into requirements for lineage specification and combinatorial action. Beyond their roles in positively driving lineage differentiation, the master hematopoietic transcription factors, often antagonize the action of factors that promote other lineages. Such cross-antagonism provides a mechanistic basis for lineage choice at each bifurcation in the hematopoietic hierarchy.

Following a general review of these findings, this presentation will focus on new findings related to the control of developmental stage-specific gene expression within a lineage. An intriguing aspect of development in the erythroid cell lineage is how fetal versus adult-stage specific gene expression is established. Two perspectives are considered. First, focusing on a specific gene locus, new findings regarding the control of the human feta-adult hemoglobin switch will be presented and discussed. These findings suggest potential strategies for directed manipulation of fetal globin silencing as therapy for the major hemoglobinopathies. Second, considering the global determinants of stage-specific gene expression, we have performed an integrated analysis of chromatin state maps, transcription factor occupancy, gene expression profiling and functional tests to identify the molecular determinants of fetal versus adult stage-specific expression. These recent experiments demonstrate that developmental stage-specific enhancers rather than promoters determine gene expression programs. Master transcription factors contribute little to stage-specificity but rather cooperate with previously unknown co-regulators to establish the relevant gene networks. The stage-specific activity of co-regulators may suggest novel approaches to manipulating or reprogramming hematopoietic differentiation.

ISEH would like to thank the supporters of the ISEH 41st Annual Scientific Meeting


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Society and Profession News

ISEH announces board of directors election results

ISEH closed its 2012 board of directors election 8 August. Nearly 120 members (or 17 percent of the membership) voted. The results were extremely close, which speaks to the high quality of candidates on the ballot.

"Our nominations committee represents the Americas, Australasia and Europe,” said Margaret A. Goodell, PhD, chair of the ISEH Nominating Committee. "We came up with a fantastic slate of nominees, all of whom have experience with and commitment to the longevity of ISEH. The very close voting for all the slots was a testament to the quality of the candidates. We are excited about the new participants who will come on board, and I am sure we will see more from the other candidates in the future.”

The results included:

Vice President

  •  Paul Frenette – 58%
  •  David Traver – 42%

    Directors: America
  •  Patricia Ernst – 59%
  •  Hector Mayani - 41%

    Directors: Europe
  • Conny Bonifer - 47%
  •  Jonas Larsson - 53%

    Directors: Pacific Rim
  •  Andrew Elefanty - 54%
  •  Atsushi Iwama - 46%

    The new leadership members will start serving their terms on 26 August, the final day of the ISEH 41st Annual Scientific Meeting.

    Outgoing board members include:

    • Past president: David Scadden;
    • Secretary/treasurer: Tao Cheng
    • Director: Timm Schroeder
    • Director: Toshio Kitamura

    Transcription Factor Lyl-1 Critical in Producing Early T-Cell Progenitors

    A transcription factor called Lyl-1 is necessary for production of the earliest cells that can become T-cells, critical cells born in the thymus that coordinate the immune response to cancer or infections, said a consortium of researchers led by those from Baylor College of Medicine in a report in the journal Nature Immunology. READ MORE

    Stem Cell Sector Validating Itself With Exciting First Half 2012

    The stem cell sector has been showing signs of life for quite some time now with the technology taking small steps at improvement via some proven efficacy and improving safety profiles. The sector has been fighting everything from embryonic stem cell controversy to the logistical concerns of consistently growing stem cells and then inducing them to differentiate into the proper cell types on demand. These "baby steps" have helped the sector walk toward its first U.S.-company approval in the form of the May 17 Osiris Therapeutics Canadian approval for the treatment of acute graft-vs-host disease (GvHD) in children. GvHD is a complication of children having bone marrow transplants and leads to mortality in up to 80 percent of those diagnosed. The approval is only the second such for the sector, following on the heels of the 2011 Korean approval for the country's FCB-Pharmacill's Hearticellgram-AMI treatment for heart attack victims. Breaking this regulatory barrier is the likely highlight for the stem cell sector in 1H 2012. However, there are several other stem cell therapy companies with significant events occurring in the first part of 2012 that should garner investor interests. These events give an indication as to where these companies stand relative to the rest of the sector and may help define stem cell therapy treatment in the coming months and years. READ MORE

    Stem Cell Opponents? Give Me Your Best Shot

    "Stem Cell Opponents? Give Me Your Best Shot” is the title of the open letter Emmy Award-winning television journalist Charles Sabine authored for the August 3 issue of Cell Stem Cell. "And what about hope? Do we HD [Huntington’s disease] families have that? The answer to that question lies in thehands of not only the researchers who are the custodians of new science, but also the legislatures, executives and churches that will dictate how our societies treat the infirm in the 21st century,” Sabine states.

    Sabine  witnessed wars and revolutions as a correspondent for NBC News. Today, he is a spokesperson for patients—and their families—suffering from neurodegenerative disease. His father died from Huntington’s disease, and Sabine and his brother took the blood test that revealed they had inherited the Huntington's gene.

    Sabine travels broadly to share the importance of work that occurs within laboratories and the need for scientists to realize how any research is valued by patients and their families. On 16 January, 2013, he presents "A Perspective on Living with Huntington's Disease,” at SLAS2013, the Society for Laboratory Automation and Screening’s five-day event, which brings together more than 4,500 laboratory science and technology scientists, academicians, business leaders and students from around the globe. Scientific session tracks include:

    • Assay Development and Screening
    • High-Throughput Technologies
    • Drug Target Biology
    • Micro- and Nanotechnologies
    • Bioanalytical Techniques
    • Informatics
    • Diagnostics

    For more information, visit the SLAS2013 website.

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    Member Profile

    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. In this issue, meet Patricia Ernst, PhD.

    Patricia Ernst Supports ISEH, New Investigators

    Patricia Ernst, PhD
    Associate Professor
    Geisel School of Medicine at Dartmouth
    Hanover, New Hampshire

    As a new ISEH Board of Directors member, Patricia Ernst, PhD, brings a special kind of enthusiasm to the board. She's a veteran with 25 years of experience but also offers a fresh, unique perspective focused on helping new investigators.

    "ISEH has put emphasis on recruiting new investigators and providing workshops and networking opportunities to help them,” she said. "I hope to help expand these opportunities to reach into the ‘in between meeting' time as well.”

    This area is special to Ernst. She realizes its importance because of her own experiences and how her mentors helped shaped her career and continue to contribute to it.

    Aside from Ernst's involvement with ISEH, she also serves as an associate professor at the Geisel School of Medicine at Dartmouth , in Hanover, N.H. Her areas of expertise include epigenetic regulators, childhood leukemia, gene regulation and hematopoiesis.

    Ernst took time out of her schedule to participate in a Q&A with Connections. Her responses below range from how she was introduced to the hematology and stem cells scientific field to the importance of mentors to what she feels is the biggest challenge currently facing the field.

    How did you find your way to the hematology and stem cells scientific field?

    Patricia Ernst: My postdoc mentor moved from Washington University to an environment at Harvard Medical School that was very rich in investigators, who were studying hematology. I found fantastic colleagues during that time that pulled my project in the hematology direction due to the excellent expertise surrounding and advising me. These colleagues are now everywhere, and I still rely on them for feedback.

    And then how were you introduced to ISEH?

    PE: Peer pressure, and I heard that meetings were awesome. After attending a few meetings myself, I realized ISEH encompasses the best colleagues in my field, and members span the entire world. I naturally have connections with some of these colleagues but ISEH helps extend this network internationally.

    You also recently joined the ISEH Board of Directors. What are your expectations and goals as a new director?

    PE: Help the society help investigators! ISEH has put emphasis on recruiting new investigators and providing workshops and networking opportunities to help them. I hope to help expand these opportunities to reach into the "in between meeting” time as well.

    Do you have any advice for someone interested in being more involved with ISEH?

    PE: The meetings have many opportunities to participate in workshops, chairing sessions, networking, etc. This kind of exposure is important for junior faculty or postdocs going on the job market. And I know I have benefitted by meeting more investigators from countries outside my own.

    ISEH, though, is all in addition to your responsibilities at the Geisel School of Medicine. What is the most exciting project currently happening at your lab/facility?

    PE: I have always been fascinated by how precise expression patterns of every necessary gene are achieved in all the different cell types we have; my current work revolves around epigenetic regulator that helps do this in different tissues differently. We are currently trying to understand one particular protein impacts on gene regulation in leukemia stem cells, normal hematopoietic stem cells and B cells, and how at the level of biochemical mechanisms it can regulate different tissue-specific programs.

    What do you consider the biggest challenge currently facing the hematology and stem cells scientific field and how can it be managed?

    PE: Maintaining momentum and funding in an uncertain environment is a challenge. Projects may have to be done at a much smaller scale than desirable in your own lab, but I hope that teaming up with other investigators is the way to overcome fewer funding opportunities.

    Given your experience in the field, how have you seen the field change in the last five years?

    PE: There is a lot work aimed at understanding transcriptional networks and the "wiring” of self-renewal, both in hematopoietic cells and other cell types, involving an unprecedented level of detail facilitated by genome-wide technologies.

    It's clear that the field is going to continue to evolve at an amazing pace. How do you see it changing over the next five years?

    PE: Much more genome-wide, high throughput types of data will hopefully yield some dust settling to reveal some fundamental principles that can be used to manipulate tissue stem cells and other stem cells for human health benefit.

    What advice do you have for new investigators getting started in the field?

    PE: Despite difficulties starting up an independent research program, always put aside some time with good mentors/advisors thinking five years ahead. When I first started my lab, Nancy Speck was an excellent mentor, not only for the constant advice and opportunities she passed my way, but also since my lab was able to meet with her group. It gave some critical mass that made the laboratory much more fun and productive.

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    Experimental Hematology

    Take a quick tour of the August and September issues and get a feel for the great scientific content. Read the full issues.

    In this Issue – August 2012

    From human pluripotent stem cells to hematopoietic cells
    Kardel et al

    There is a significant clinical interest in generation of hematopoietic cells from human pluripotent stem cells for therapeutic purposes. The establishment of a robust and reproducible large-scale in vitro production system will also be a useful tool for studying the ontogeny of hematopoiesis and modeling of human diseases. In this critical review, Kardel et al highlight the major recent advances in the generation of hematopoietic cells from human ES and iPS cells and discuss the challenges that remain and their potential causes. This review provides an interesting reading for anybody looking to update their knowledge of the field.

    Tyrosine kinase inhibitors as immunomodulatory agents
    Blake et al

    The protein tyrosine kinase inhibitors Dasatinib and Imatinib are widely used in the treatment of Chronic Myelogenous Leukemia and Philadelphia chromosome-positive Acute Lymphoblastic Leukemia. In addition, they inhibit T-cell proliferation by inhibiting lymphocyte cell-specific tyrosine kinase - Dasatinib more potently than Imatinib. This unique immunomodulatory activity may broaden their therapeutic potential for other diseases. In this study, Blake et al documented that Cyclosporine A (CsA), another agent blocking T cell proliferation, showed a potent synergistic inhibitory activity of T cell proliferation when combined with Dasatinib or Imatinib. Interestingly, however, when T cells were stimulated with anti-CD3 and anti-CD28 antibodies, this interaction was antagonistic, such that Dasatinib enhanced T cell proliferation even at low concentrations. Quantitative analysis of drug interactions with similar immunomodulatory properties is important in optimizing drug dosages that will achieve maximum efficacy with minimum toxicity, as well as provide novel therapeutic alternatives in the treatment of autoimmune diseases, GVHD and transplant allograft rejection.

    An unusual role of NUP98-HOXD13 Leukemic Fusion Gene: immune dysregulation
    Puthiyaveetil et al

    Studies in mice have shown that NUP98HOXD13 (NHD13) fusion gene cause Myelodysplastic Syndrome (MDS). In addition, NHD13 transgenic mice have impaired lymphocyte differentiation resulting in reduced peripheral T lymphocytes, increased levels of IgM and reduced IgG1 and IgE. In this study, Puthiyaveetil et al uncovered the potential mechanism by which NHD13 affect B lymphocyte development and function. They showed that NHD13 impaired class switch recombination, the biological mechanism that changes a B cell's production of antibody from one class to another and reduced the antibody-mediated immune response. This defective antibody-mediated immune response could also be due to the defective interaction of T cells with B cells in these mice. Such studies addressing the mechanism of immune defects observed in the presence of fusion proteins are highly valuable because they provide greater insight into the etiology of compromised immunity in many patients with MDS and leukemia, and importantly, offer therapeutic targets that may prove useful in the management of patients with these chromosomal mutations and other immunodeficiencies.

    In this Issue – September 2012

    IGF signaling in AML
    Jenkins et al

    Insulin-like growth factor (IGF) signaling plays an important role in the growth of many types of cancer cells and of normal tissues during development. IGF1R is highly expressed in normal hematopoietic and AML stem cells. In their earlier work, these investigators had documented that IGF signaling played a significant role both in the establishment and maintenance of NOTCH1 T-ALL in mice. In the current study, Jenkins et al investigated the role of IGF signaling in a murine MLL-AF9 model of myeloid leukemia. They showed that IGF1R signaling contributed to the oncogenic transformation of normal myeloid progenitor cells and that decreased IGF1R expression significantly impaired malignant transformation of committed granulocyte-monocyte progenitors. Surprisingly, however, IGF signaling was not required for the maintenance of the myeloid leukemia clone once it was established. IGF1R has become an attractive therapeutic target in AML, as it is one of the most abundantly phosphorylated receptor tyrosine kinases in AML cells and its expression correlates with the cells' chemotherapy resistance. Several small molecule tyrosine kinase inhibitor and blocking antibody therapies targeting IGF1R have been developed that showed activity against AML cells in pre-clinical studies. However, based on the findings of this study, it is quite possible that the efficacy of these agents may in fact be due to their activity against tyrosine kinases other than IGF1R, and thus, a better understanding of their mechanism of action is required. Moreover, before IGF1R inhibitor can be tested in clinical trials, further investigation is required into the role of IGF1R signaling in other AML models.

    The promise of phosphoprotein profiling in CML patients
    Jalkanen et al

    With the discovery of tyrosine kinase inhibitors, the treatment outcomes for CML patients have dramatically improved; however, some patients still fail to achieve molecular response. Identifying these "poor responders" up-front at diagnosis and adjusting their treatment accordingly will improve their survival. In this study, Jalkanen et al used phosphoproteomic profiling to show that patients who failed to achieve molecular response following Imatinib treatment had a distinct phosphorylation pattern in the bone marrow at diagnosis, and most significantly, they had increased phosphorylation of STAT5b, PLC-1, Pyk2, Hck and Paxillin. The scientific community should expedite its efforts to validate whether pSTAT5b or any other highly phosphorylated protein can be used as a biomarker in guiding therapy at diagnosis for suboptimally responding patients. This will save CML patients' lives, as well as healthcare dollars.

    Persistent Etv2 expression in mice perturbs vasculogenesis and hematopoiesis
    Hayashi et al

    During embryogenesis, the ETS domain transcription factor Etv2 plays a critical role in the initiation of vascular and blood development from mesodermal cells. Due to this crucial role in promoting hematopoiesis/vasculogenesis, the manipulation of Etv2 expression in ES or iPS cells presents a promising strategy for the generation of endothelial or hematopoietic progenitor cells for cellular therapies. In this study, Hayashi et al showed that constitutive Etv2 expression during embryonic development perturbed vascular development and hematopoiesis. In adult bone marrow cells, it favored endotheliazation and suppressed hematopoiesis, with erythropoiesis more severely reduced than myelopoiesis. This study once again highlighted the notion that Etv2 expression is tightly regulated and that its transient expression is necessary to achieve normal vascular development and hematopoiesis during embryogenesis. Based on these results, the manipulation of Etv2 for cellular therapies would require the development of methods for its transient delivery into the cells.

    Manuscripts encouraged
    Spread the wealth of your knowledge by submitting a manuscript to Experimental Hematology.

    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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