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

In the June 2012 Issue

Annual Scientific Meeting
Book your travel arrangements today
Late-breaking abstracts deadline is 6 July

Experimental Hematology
Explore key manuscripts in the June and July issues

New Investigators
ISEH enhances new investigator programming at Annual Scientific Meeting

Society and Profession News
Be a Part of Something Big
SLAS2013 session interests ISEH members
Bioengineered myocardium derived from induced pluripotent stem cells improves cardiac function and attenuates cardiac remodeling following chronic myocardial infarction in rats
Aged hematopoietic stem cells rejuvenated to be functionally younger

Member Profile
Susie Nilsson: 'Don't be a follower'

Annual Scientific Meeting

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

Online highlights:

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.

Late-breaking abstracts deadline is 6 July

Did you miss the initial abstract submission deadline? You still have the opportunity to submit your abstract and present at the ISEH 41st Annual Scientific Meeting during the late breaking call for abstracts from 4 June to 6 July. Share your research, experiences, challenges, and fresh approaches with your professional colleagues from around the world at the premier meeting for hematology and stem cell professionals. READ MORE

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Experimental Hematology

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

In this Issue – June 2012

Functional role of UTX in normal and malignant hematopoiesis
Liu et al

Ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX, also known as KDM6A), encodes an H3K27Me2/3 demethylase, which plays an important role in development, self renewal and cardiac differentiation. UTX protein has tumor repressor properties, its deficiency results in embryonic lethality in mice, and somatic mutations have been identified in multiple hematological malignancies and many types of leukemia cell lines. In this study, Liu et al showed that knockdown of UTX in primary murine bone marrow cells impaired their clonogenic potential probably by regulating the expression levels of Mll1, Runx1 and Scl, which are genes frequently involved in leukemogenesis. UTX seems to directly associate with their promoters to regulate the methylation of H3K27 at these loci. Moreover, they showed that UTX depletion in several types of human leukemia cell lines also severely impaired their proliferative capacity. Epigenetic deregulation plays an important role in tumorigenesis and leukemogenesis. Thus, a better understanding of the exact molecular changes that occur in these pathways should provide additional targets for developing novel agents which can be combined with already existing epigenetic modifiers to reverse epigenetic alteration with maximum potency.

Improved cord blood engraftment: Ex vivo fucosylation revisited
Robinson et al

Advantages to HLA-matched unrelated donor CB transplants (UCBT) include a broad source of cells from worldwide public CB banks and relatively low rates of serious graft-versus-host disease (GvHD), due to the greater HLA disparity tolerated. However, a major obstacle slowing down the broader use of UCBT in adults remains the delayed engraftment resulting in significantly increased morbidity and mortality during the immediate post transplant period. Delayed engraftment is thought to be due to both low CD34+ cell dose transplanted and a homing defect of CD34+cells to BM. The latter is thought to be due to low fucosylation of cell surface integrins, resulting in decreased interaction between CD34+ cells and selectins expressed by BM endothelium. An earlier study in Blood 2004 by Xia et al reported that treatment of CB CD34+cells with guanosine diphosphate (GDP) fucose and exogenous alpha1-3 fucosyltransferase VI (FT-VI) enhanced engraftment of human hematopoietic cells by a 2-fold in BM of NOD/SCID mice, when analyzed six weeks post transplant. However, a subsequent study by Hidalgo et al failed to show any benefit of fucosylation in the homing of CB CD34+ cells to BM of NOD/SCID mice analyzed 12-16h post transplant. In this study, Robinson et al first showed that only fucosylated CD34+ cells were responsible for engraftment in NSG mice. They later fucosylated CB CD34+ ex vivo by incubation in FT-VI and its substrate (GDP-fucose) for 30 minutes. This quick and simple treatment clearly enhanced both the rate and level of human multi lineage, long-term engraftment in BM of NSG mice. Ex vivo fucosylation of CB cells seems a promising effective method capable of enhancing engraftment in UCBTrecipients, and therefore, it should be pursued more aggressively in clinical settings. Such efforts that broaden the utility of UCBT and that offer a therapeutic alternative are highly needed to help adult patients who otherwise succumb to their diseases due to the lack of a suitable donor.

In this Issue – July 2012

The new erythropoiesis stimulating agent Peginesatide is a functional analog of erythropoietin

Green et al

The use of recombinant human erythropoietin (rHuEPO) has revolutionized the treatment of anemia in patients with chronic kidney diseases and some cancers. To improve compliance, erythropoiesis stimulating agents (ESA) need to have long half life in vivo, while maintaining their maximum efficacy and safety. Until recently, Darbpoetin alfa was the only longer acting ESA available in North America, and needed to be injected at least once in two weeks to keep hemoglobin levels at an optimum level. The ESA Peginesatide, formerly called Hematide, has recently been approved by the FDA. It is a novel synthetic PEGylated compound with no sequence similarity to erythropoietin; however, it acts as a functional analog of erythropoietin by binding to and stimulating the erythropoietin receptor. This molecule is immunologically distinct from the other ESAs, and has no cross-reactivity with anti-erythropoietin antibodies. Moreover, clinical studies have shown that once-a-month dosing was sufficient to control anemia in patients with kidney diseases. In this study, Green et al documented expression of similar set of target genes and phosphoproteins following treatment with Peginesatide or rHuEPO. Moreover, they showed that the compounds activated very similar signaling pathways, mainly JAK/STAT, MAP kinase and PI3 kinase pathways. This study fills a big gap by documenting in great detail the biological function of Peginesatide and how it is closely related to rHuEPO, an ESA that has been in the clinic for a long time and has substantial long term outcome data available. The information provided in this study will be indispensable when coupled with long term outcome data that will be gathered with the increased use of Peginesatide in the future. Efforts in finding novel, safe and efficacious agents with even longer half life should continue. The discovery of such agents would further impact patient compliance and health care costs for the treatment of chronic anemia in certain settings.

Panobinostat-induced thrombocytopenia; hyperacetylated tubulin is a key player
Iancu-Rubin et al

Panobinostat (LBH589), a non selective histone deacetylase inhibitor with promising anticancer activity, is currently in clinical trials for patients with several hematological malignancies and solid tumors. However, thrombocytopenia with unclear etiology remains its major dose-limiting toxicity. In this study, Iancu-Rubin et al showed that LBH589 did not affect megakaryocyte (MK) lineage commitment or proliferation, but inhibited MK maturation and platelet formation. Surprisingly, this was mediated by hyperacetylation of tubulin, a nonhistone protein which plays an important role in microtubule dynamics and organization essential for MK maturation and platelet formation. This study, while shedding light into the mechanisms underlying LBH589-induced thrombocytopenia, highlights another potential use for histone deacetylase inhibitors by targeting tubulin for the treatment of thrombocytosis in patients with myeloproliferative neoplasms. Better understanding of the mechanism of action of therapeutic agents may, at times, offer therapeutic alternatives for unrelated diseases.

Deletion of the Scl +19 enhancer expands hematopoietic stem and progenitor cells
Spensberger et al

The stem cell leukemia (Scl) gene is expressed in hematopoietic stem cells (HSCs), progenitors, erythroid, megakaryocytic and mast cells. Scl is essential for normal blood and endothelial development, but its deletion in adult HSCs results in mild phenotype with some increase in HSC numbers, as well as a mild impairment in the repopulation potential of ST-HSCs, and some mild defects in erythropoiesis and megakaryopoiesis. Previous studies have confirmed that the Scl +19 enhancer (located 19 kb downstream of the Scl promoter) is the key element driving the expression of Scl during development, as well as in adult HSCs, progenitors, megakaryocytes, and mast cells, but not in mature erythroid cells. In this study, Spensberger et al studied the function of the Scl +19 enhancer within the context of the endogenous locus, and showed that Scl∆19/∆19 mice were viable and had significantly higher number of HSCs in their bone marrow, mainly 34+ ST-HSCs and megakaryocyte-erythroid progenitors. The differentiation potential of these progenitor cells remained normal. Further analysis of Scl expression profile and chromatin modification status in mutant cells suggested the redundancy of the Scl +19 regulatory element and the activation of post-transcriptional and post-translational compensatory mechanisms. This may explain why deletion of Scl +19 and other vital regulatory elements often result in a mild phenotype. One now wonders whether we could take advantage of inducible deletion of the Scl +19 enhancer for its stem cell expansion potential.

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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New Investigators

ISEH enhances new investigator programming at Annual Scientific Meeting

ISEH continues to provide opportunities for young scientists to help them grow in their careers, including facilitating mentoring relationships with established ISEH scientists. The New Investigator Committee is committed to creating opportunities for junior scientists to grow in their careers and become future leaders of the industry and ISEH. Below are two samples of rewarding opportunities for new investigators at the ISEH 41st Annual Scientific Meeting. For more information about other events, visit the 2012 Meeting New Investigators page at ISEH's website.

New Investigator Networking Rendezvous
Food, drinks, networking, and fun will be the main attraction at Cafe-Restaurant de Overkant, located a short walking distance from the Hotel Okura. Enjoy this unique social gathering with a professional flair! Cost is $25. (~19 EUR).

New in 2012
The New Investigator Committee is sponsoring an invited speaker session featuring Derrick Rossi, PhD, Harvard Stem Cell Institute, USA. He will present "Genetic and Epigenetic Mechanisms Underlie Hematopoietic Stem Cell Aging.” 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, Rossi will present evidence that both epigenetic and genetic mechanisms contribute to HSC aging.

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Society and Profession News

Be a Part of Something Big

Connecting clinicians and researchers from around the world, ISEH is an inclusive, international forum that creates many opportunities for conversations between leaders in the field, new scientists and industry. The Society has more than 600 active members from 40 countries around the world.

Members share the latest scientific information and remain at the forefront of advances in experimental hematology in areas such as progenitor cells, hematopoiesis, growth factors and cytokines; immunology; mechanisms of hematologic malignancies (leukemias, lymphomas, myelomas); oncology; oncogenes; stem cell niches; cancer stem cells; gene profiling (microarray chips) and protein chips; stem cell biology and transplantation (bone marrow, peripheral blood, cord blood); cellular therapy; gene therapy; and hematopoietic microenvironment.

Have you secured your spot by renewing your membership for 2012? If not, click here to do so today!

SLAS2013 session interests ISEH members

One session at the Society for Laboratory Automation and Screening's annual event, SLAS2013, 12-16 January, 2013, Orlando, FL, USA, may be of special interest to ISEH members.

Chaired by Petr Bartumek, the session focuses on cell-based assay development and will include cell-based approaches to targets such as G protein coupled receptors, ion channels and transporters; cell-based ultra high-throughput screening and reporter assay formats; stem cells and/or primary cells for high-throughput screening; and cancer drug combination screening and/or synthetic lethal screening. Bartumek is coordinator of the Center for Chemical Genetics at the Institute of Molecular Genetics, Prague, Czech Republic.

This session is part of the Assay Development and Screening track, one of seven tracks at SLAS2013. The SLAS2013 call for abstracts is open until July 30 for podium presentations and 31 December for poster presentations.

SLAS2013 is a five-day event bringing together more than 5,500 laboratory science and technology scientists, academicians, business leaders, and students from around the globe.

Bioengineered myocardium derived from induced pluripotent stem cells improves cardiac function and attenuates cardiac remodeling following chronic myocardial infarction in rats

Cell-based therapies are promising strategies for myocardial repair following myocardial infarction. Induced pluripotent stem (iPS) cells have the potential to generate many cardiomyocytes, and they hold significant promise for the application of regenerative medicine to heart failure. Here, we developed cardiac tissue sheets, termed bioengineered myocardium (BM), from mouse iPS cells and measured cardiac performance following BM implantation in a rat chronic myocardial infarction model. Immunostaining analyses revealed that the α-actinin+ cell population was isolated with more than 99 percent purity under specific culture conditions. To evaluate the contribution of BM to the improvements in cardiac performance, we induced myocardial infarction in 30 F344/NJcl-rnu/rnu rats by left anterior descending coronary ligation. The rats were randomly divided into two groups, two weeks after ligation: a BM implantation group (n = 15) and a sham group (n = 15). Echocardiography and catheter examination showed that the BM implantation significantly improved cardiac function and attenuated cardiac remodeling compared with the sham group. Histological analyses demonstrated that the implanted BM survived at the epicardial implantation site four weeks after implantation. The implanted BM survived and attenuated left ventricular remodeling in the rat chronic myocardial infarction model. Thus, BM derived from iPS cells might be a promising new treatment for heart failure. READ MORE

Aged hematopoietic stem cells rejuvenated to be functionally younger

Researchers have rejuvenated aged hematopoietic stem cells to be functionally younger, offering intriguing clues into how medicine might one day fend off some of the ailments of old age.

Scientists at Cincinnati Children's Hospital Medical Center and the Ulm University Medicine in Germany report their findings online May 3 in the journal Cell Stem Cell. The paper brings new perspective to what has been a life science controversy – countering what used to be broad consensus that the aging of hematopoietic stem cells (HSCs) was locked in by nature and not reversible by therapeutic intervention.

HSCs are stem cells that originate in the bone marrow and generate all of the body's red and white blood cells and platelets. They are an essential support mechanism of blood cells and the immune system. As humans and other species age, HSCs become more numerous but less effective at regenerating blood cells and immune cells. This makes older people more susceptible to infections and disease, including leukemia. READ MORE

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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 Susie Nilsson, PhD. She is a 20-year hematology and stem cells scientific field veteran. She's also been a member of ISEH for 20 years and was the chair of the 2012 ISEH Annual Scientific Meeting in Melbourne, Australia.

‘Don't be a follower'

By Dennis Coyle,
Editor, Connections in Hematology & Stem Cells

Susie Nilsson, PhD

Principal Investigator
Stem Cell Laboratories
Melbourne, Victoria

After 20 years in the hematology and stem cells scientific field, Susie Nilsson, PhD, has experienced her fair share of challenges, but she never gave up and continued to pave her own path. And that is what she recommends to any new investigator entering this field.

"You will always get knock backs and encounter difficulties,” Nilsson said. "You just have to continue to get back up and keep trying. Trust your gut and work on something novel. Don't be a follower.”

Nilsson's drive and determination has served herself well over the years. She's now principal investigator, Stem Cell Laboratories at the Commonwealth Scientific and Industrial Research Organisation (CSIRO), Australia's national science agency located in Melbourne, Victoria. Her areas of expertise includes bone marrow niche, bone marrow transplantation and stem cells.

In addition to her work at CSIRO, Nilsson is also extremely involved with ISEH. She's a 20-year member and served at several different volunteer capacities with the society, including board member, chair of local organizing committee ISEH 2010, Scientific Organizing Committee, associate editor, Nominating Committee member, and chair of the Emerging Leaders Taskforce.

Nilsson took time away from her busy schedule to talk to Connections in Hematology & Stem Cells. The interview covered how she entered the field to how she feels the field will change over the next several years.

Connections: There are a lot of interesting aspects of this scientific field; what do you find the most exciting?

Susie Nilsson: At the basic biology level, the interaction between the HSC and its microenvironment. Specifically, how the environment educates and regulates HSC. In the translational space, the promise of new and exciting cellular therapies reaching the clinic.

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

SN: An emphasis on the microenvironment of the cell being critical for its potential and regulation. In addition a shift to ES and or iPS derived hemopoietic cells.

C: 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?

SN: The reality as to whether ES or iPS differentiated hemopoietic stem cells are in fact equivalent to their adult counterparts will be determined. More cellular therapies will hopefully enter the clinic. Continuing to see a better understanding of the hemopoietic microenvironmental components and their ability to interact with HSC.

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

SN: Educating the public about the hope and hype of the field so that we do not over promise and under deliver on expectations; managing stem cell tourism; and maintaining the excitement in the area so that the funding agencies continue to see reasons to provide money.

C: In addition to your work at CSIRO, you are also quite involved with ISEH and served as chair of the 2010 ISEH Annual Scientific Meeting in Melbourne, Australia. How did you get involved with ISEH?

SN: I first got involved with ISEH because my PhD supervisor, Ivan Bertoncello, was heavily involved in the society and recognized its value for students to meet and interact with the leaders in the field. I entered and won the societies "Distinguished New Investigator Award” in the first year I attended and have never not been involved since.

C: The 2010 event was considered very successful. What do you think made it so memorable?

SN: The freely available yet excellent standard coffee carts! The science that was presented was really good, including all the invited speakers. The location was also really good, as was the catering. In addition, the company representation made a great difference to the atmosphere.

C: Why do you continue to attend ISEH Annual Scientific Meetings?

SN: The size of the meeting is perfect for optimal interactions for both students and senior scientists. Scientific quality is always excellent, and leaders in the field attend.

C: How would you describe the funding climate for your specific type of research?

SN: It could always be better, but everyone would say that about their area of science. Stem cells have had so much hope put on them, if expectations for delivery (especially in the ES and iPS area) are not met, the funding money may dry up.

C: What advice do you have for new investigators entering this scientific field?

SN: You will always get knock backs and encounter difficulties; you just have to continue to get back up and keep trying. Trust your gut and work on something novel. Don't be a follower.

You can connect with Susie Nilsson, now through the ISEH member database. Click here to contact her or to build your personal profile. You can also learn more about Commonwealth Scientific and Industrial Research Organisation (CSIRO).

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