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

In the April 2012 Issue

Annual Scientific Meeting
Call for abstracts deadline is 29 April
Program highlight: Hematopoietic stem cell microenvironments

Experimental Hematology
Explore key manuscripts in the April and May issues

New Investigators
ISEH invites new investigators to ‘Meet the Professor' event

Society News
Meeting Report: American Association of Cancer Research Annual Meeting
Be a part of something big 
SLAS releases call for abstracts

Member Profile
Meet Timm Schroeder, Ph.D., a McCulloch and Till Award Winner

Annual Scientific Meeting

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

Online highlights:

Call for abstracts deadline is 29 April

Presenting to the ISEH audience is advantageous to advancing your ideas and quality hard work in the field of hematology and stem cells. The 41st Annual Scientific Meeting call for abstracts closes 29 April. Presentations selected for the meeting also are published in an Experimental Hematology supplement. The selection committee has identified the following areas as key to the 2012 meeting program: developmental biology (both mammalian and other animal models), ES/iPS cells, epigenetics, leukemia/lymphoma, microenvironment, novel tools/approaches in hematology, transcriptional/translational control of hematopoiesis and transplantation/gene therapy/regenerative medicine.

Abstract length is maximum 2,500 characters and can include two tables and two graphs. Members can submit abstracts free; there will be a $50 fee for non-members to submit abstracts. From 10 June to 8 July, ISEH will accept late-breaking abstract submissions. READ MORE

Program highlight: Hematopoietic stem cell microenvironments Headline
By P. Frenette, Ruth L., and David S. Gottesman
Institute for Stem Cell and Regenerative Medicine, Albert Einstein College of Medicine, New York, NY

Editor's Note: The following is an abstract outlining Frenette and Gottesman's presentation at the ISEH 41st Annual Scientific Meeting. A list of speakers is available online and will be frequently updated.

Hematopoiesis is tightly orchestrated by specific microenvironments that regulate hematopoietic stem cell (HSC) differentiation and self-renewal to produce daily billions of cells for life. HSCs are localized in specific niches controlled by local factors and long-distance cues from hormones or nerves. Innervation from the sympathetic nervous system (SNS) regulates the trafficking of HSCs and progenitors by acting on beta-adrenoreceptors expressed on the niche cells, thereby controlling the expression of "retention factors.” Local adrenergic activity indeed controls diurnal oscillations in the expression of these retention factors, allowing circadian release of HSCs and differentiated progeny in blood. Release of HSCs in blood occurs at relatively low levels under steady-state conditions but it can be dramatically enhanced by the administration of G-CSF, the most commonly used method to harvest HSC from blood for clinical transplantation.

Further studies have revealed that self-renewing perivascular mesenchymal stem cells (MSC), targeted by the SNS, represent a candidate niche cell that can be prospectively identified by transgenic expression of GFP under the Nestin promoter. Thus, the two existing stem cell types in the bone marrow form a self-regulating unit. This unit is influenced by other hematopoietic cells such as CD169+ macrophages, which promote the expression of HSC retention factors by nestin+ niche cells, suggesting two opposing regulatory arms controlling HSC retention in the BM where the SNS constitutively promote egress by reducing the expression of retention factors by MSCs whereas macrophages have the opposite effect.

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Experimental Hematology

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

In this Issue – April 2012

A highly valuable research tool: Mx-cre transgenic mice
Lu et al and Keel et al

Since they were first reported in 1995, Mx-cre transgenic mice harboring a target gene flanked by loxP recognition sites (floxed) have been widely used for inducible inactivation, at any time during development or adult life, of genes which knockdown resulted in embryonic lethality. Two papers in this issue have taken advantage of this powerful tool. In the first study, Lu et al investigated the role of Focal adhesion kinase (Fak) in steady state hematopoiesis in Fakfl/flMx1-cre+ mice. Fak is a non-receptor protein tyrosine kinase involved in multiple cellular processes, such as growth, survival and adhesion. Their studies indicated that Fak was not essential for steady state hematopoiesis and that its inactivation in both bone marrow and bone marrow niche cells did not have any impact on long-term repopulating cells, whereas its inactivation led to a modest increase in the number of cycling, short-term repopulating cells. These findings suggest that Fak may potentially play a role in maintaining quiescence of hematopoietic stem cells by regulating their adhesion to the microenvironment via integrin and CXCL12 interaction.

In the second study, Keel et al developed mice with a conditional deletion of one allele of the ribosomal protein Rps6. Interestingly, even though this deletion was not previously reported in patients with myelodysplastic syndrome (MDS) or Diamond-Blackfan anemia (DBA), the Rps6flox/floxMx1-cre mice recapitulated the hallmark erythroid phenotype of both DBA and 5q- MDS: hypoproliferative macrocytic anemia. These mice also displayed additional hematopoietic defects, such as thrombocytosis, granulocytopenia, lymphopenia and an elevated erythrocyte adenosine deaminase activity. Similar findings have recently been reported by Mc Gowan et al in Blood in Sep 2011. Keel et al went one step ahead and treated Rps6 hemizygous mice with lenalidomide or steroids, major drugs used in patients with MDS or DBA, respectively. They showed that anemia in these mice improved in response to lenalidomide but not to steroid therapy. Ribosomal protein haploinsufficiencies and/or ribosome biogenesis defects play a significant role in the pathogenesis of MDS and DBA, but the exact mechanism of their impact on erythropoiesis remains unknown. The availability of such animal models that recapitulate the diseases' phenotype is critical in enhancing our understanding of their pathobiology. They should also prove useful in helping to find novel pathways and candidate molecules that can be targeted for development of novel therapeutics.

A new mouse model of MDS in mice heterozygous for CREB binding protein
Zimmer et al

Myelodysplastic syndrome (MDS) is a heterogeneous group of preleukemic diseases in which a clonal defect in hematopoietic stem cellss manifest itself with abnormal differentiation in one or more blood lineages. CREB binding protein (CREBBP) has been reported in chromosomal translocations found in patients with therapy-related MDS and acute myeloid leukemia (AML). Moreover, these investigators have previously reported that Crebbp+/- mice have an increased incidence of hematological malignancies, suggesting that CREBBP may play a role in the pathogenesis of MDS and AML. This is probably mediated by its ability to facilitate DNA damage repair by chromatin remodeling through its histone acetyltransferase activity and by enhancing the function of many DNA damage response/repair proteins. In this study, Zimmer et al showed that Crebbp+/- mice develop, within nine to 12 months of age, MDS/MPN prior to developing a hematological malignancy and that they are also hypersensitive to -radiation. They documented that this is, at least, in part, due to deficient DNA repair, as revealed by a marked decrease in key proteins involved in base excision repair in their bone marrow stem and progenitor cells. This novel mouse model of MDS/MPN will be a valuable tool for the field. It will help advance our understanding of the pathogenesis of this highly complex spectrum of diseases and expedite the efforts of finding a cure for these desperate patients.

In this Issue – May 2012

Better killing of CML LSCs: Combining an apoptotic agent with tyrosine kinase inhibitors (TKI)

Airiau et al

The discovery of TKIs has revolutionized the treatment of patients with CML, but these agents have some limitations. Indeed, lifelong therapy is needed due to their insufficiency to eliminate quiescent LSCs, and some patients are resistant or can develop resistance over time. Many studies are now focusing on novel strategies that combine TKIs with agents targeting alternate pathways to provide stronger antileukemic activity and to better eradicate CML LSCs. ABT-737, a selective inhibitor of Bcl-2, Bcl-xL and Bcl-w, induces apoptosis in a broad range of hematologic malignancies. An orally bioavailable derivative of ABT-737 (Navitoclax) is in phase I/II clinical trials as a single agent for relapsed or refractory chronic lymphocytic leukemia and other lymphoid malignancies and for advanced small cell lung cancer. In this study, Airiau et al showed that combining ABT-737 with imatinib or nilotinib, two commonly used TKIs, increased apoptosis in CML cell lines and in patients' bone marrow quiescent CD34+38- cells TKI-insensitive population. Their detailed analysis revealed that increased apoptosis in these cells was due to decreased anti-apoptotic XIAP protein and caspase-3 activation. These findings correlated well with results recently reported by Mak et al in 2011 in Leukemia, in which they also showed that combination of ABT-737 with imatinib synergistically induced more killing of quiescent CD34+CD38- cells from TKI-resistant CML patients in blast crisis. Furthermore, the present study extended these observations to an additional TKI, nilotinib. Both studies provide evidence that combination targeted therapies hold promise for effective elimination of LSC in CML, resulting in better outcome in these patients, and therefore their translation into clinical use should be expedited.

The role of p45 NF-E2 in erythroid differentiation
Gasiorek et al

The transcription factor p45 nuclear factor-erythroid-derived 2 (NF-E2) is a basic-leucine zipper transcription factor that plays major roles in erythroid and megakaryocytic lineages. Previous knockout mouse studies showed that p45 NF-E2 played an important role in erythroid differentiation, including the control of - and -globin gene expression, as well as in megakaryocte biogenesis. Loss of p45 NF-E2 resulted in the absence of circulating platelets, which led to the death of most animals due to hemorrhage shortly after birth. Even though these neonates were also severely anemic and had red cell defects, surviving adults had a mild anemia with slightly decreased hemoglobin levels. In this study, Gasiorek et al focused on the terminal erythroid differentiation and showed that mice lacking p45 NF-E2 displayed abnormal erythroid differentiation in the bone marrow, increased GATA1 expression and inhibition of cell cycle progression leading to compensatory increased in splenic erythropoiesis driven by upregulated EPO levels. This interesting study adds another layer to the role of p45 NF-E2 in erythroid differentiation.

A novel population of lymphoid progenitors in mouse lymph node
Warner et al

Natural killer (NK) cells, part of the innate immune system, can kill tumor and virally infected cells without previous priming, and therefore represent a promising tool for the treatment of cancer. As interest in NK cell immunotherapy is growing, significant effort is put in studies that would lead to their better characterization, purification and expansion. In this study, Warner et al identified a novel population of lymphoid progenitors in the lymph node of normal mouse (lymph node lymphoid progenitors, LNLPs), which were phenotypically very similar to bone marrow common lymphoid progenitors (BM CLPs): they lacked lineage markers, expressed CD127 and low levels of CD117 and Sca-1. LNLPs were different from previously identified LN NK progenitors as they lacked CD49b. LNLPs had NK and T cell potentials and they preferentially differentiated into NK cells in the lymph node, whereas BM CLPs developed mostly into B cells. Such studies that enhance our understanding of NK cell development in vivo are crucial in exploiting NK cell-based immunotherapy for cancer.

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 invites new investigators to 'Meet the Professor Lunch'

ISEH's new Meet the Professor Lunch will feature six professors available for discussion over lunch. Be sure to register for the 41st Annual Scientific Meeting for a spot with your preferred professor, which you can select when you complete the meeting registration process.

Confirmed professors include:

  • Paul Frenette, Albert Einstein College of Medicine, USA;
  • Tessa Holyoake, University of Glasgow, UK;
  • Derrick Rossi, Harvard, USA;
  • Timm Schroeder, Helmholtz Center Munich, Germany;
  • Constanze Bonifer, University of Birmingham, UK; and
  • Stefan Karlsson, Lund University, Sweden.

ISEH continues to provide opportunities for new scientists to grow in their careers, including facilitating mentoring relationships with established ISEH scientists. ISEH's 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. For more information, visit the 2012 Meeting New Investigators webpage.

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Society News

Meeting report: American Association of Cancer Research Annual Meeting

Contributed by Keith Humphries MD, Ph.D. (British Columbia Cancer Agency and Editor-in-Chief, Experimental Hematology)

Perhaps I have been one of the rare people to think that American Association of Cancer Research (AACR) meetings were mainly the domain of those interested in solid tumors. My attendance at this year's meeting held March 31-April 4 in Chicago certainly dispelled me of that notion with the field of hematology and stem cells penetrating education, major and minor symposia and poster sessions.

The count of presentations on the topic of Acute Myeloid Leukemia alone was more than 250, and I lost count of those on the topic of cancer stem cells, many of which focused on the leukemia paradigm. Just to give a flavor of this content, some of the session titles included: Regulation of Cancer Stem Cells; Therapeutic Targeting of Cancer Stem Cells; Stem Cells and Epigenetics; Cell of Origin and Plasticity of Cancer Stem Cells.

I had the privilege of speaking at an education session organized by Dr. Connie Eaves, a long-time member or ISEH, on the topic of Cancer Stem Cells – New Insights from New Approaches. As an aside, anyone interested in the topic of cancer stem cells would do well to read Dr. Eaves' recent review on the history of the concept (NguyenLV et al Nat Rev Cancer 12: 133-143, 2012).

At this session, Dr. Ali Turhan, Poitiers University Hospital (Poitiers, France), provided an elegant summary of cancer stem cells seen through the lens of chronic myelogenous leukemia. True to the title of his talk, CML has indeed been a lead paradigm of the cancer stem cell model, helping to explain the difficulty of irradicating the disease with kinase inhibitors and providing one of the clearest examples of disease origin from a preexisting stem cell and progression from acquired mutations in later cells in the hierarchy (e.g. see Chomel JC et al Blood 118: 3657-3660, 2011).

My talk focused on murine models of leukemia engineered by the potent oncogenes MN1 and Hox transcription factors. Here the lessons learned include extreme variation in the functional potency of leukemic stem cells depending on the nature of the oncogenic hits and the identification of genes such as Meis1 that are key to a cell's susceptibility to conversion to a leukemic stem cell ( e.g. see Heuser M et al Cancer Cell 20: 39-52, 2011; Heuser M et al, Exp Hematol 38: 174-170, 2010).

Work presented in this session by Dr. Hanno Glimm, the National Center for Tumor Diseases (Heidelberg, Germany), showed how the leukemic stem cell paradigm could be extended to the setting of human colon cancer with the ability to enrich for colon cancer stem cells and initiate cancer in xenograft models. An interesting aspect of this talk was that Dr. Glimm is himself a hematologist with notable contributions to the hematopoietic stem cell field, now applying his expertise to the solid tumour problem (e.g see Dieter SM et al, Cell Stem Cell 9:357-365, 2011).

The final talk in this session was given by Kerstin Sinkevicius, the lab of Carla Kim at the Children's Hospital Boston (Boston, MA). Here the focus was on lung cancer stem cells particularly in the context of metastasis. Again the lessons learned from the field of hematologic malignancies have guided approaches to enrich and functionally characterize the lung cancer stem cell. Indeed some of the key genes involved in hematopoietic stem cell function such as Bmi-1 are emerging as equally important in this setting (e.g. see Zacharek SJ et al, Cell Stem Cell 9:272- 281, 2011).

For those interested in finding out more about what went on at the meeting, I encourage you to visit AACR's website. Hopefully upcoming reviews in Experimental Hematology will provide more coverage on the still evolving field of cancer stem cells and the all important quest for targeting these for more effective therapies.

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, young scientists and industry. The Society has more than 800 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!

SLAS releases call for abstracts

January 12-16, 2013
Orlando, FL, USA
Society for Laboratory Automation and Screening

The SLAS2013 Annual Conference Program Committee invites your abstract submission, which will be considered for SLAS2013!

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. Scientific session tracks include:

· Assay Development and Screening;

· High-Throughput Technologies;

· Drug Target Biology;

· Micro- and Nanotechnologies;

· Bioanalytical Techniques;

· Informatics; and

· Diagnostics.

"ISEH member expertise in the areas of hematology, immunology, stem cell research, cell and gene therapy is welcomed at SLAS2013,” said Steve Hamilton, SLAS director of education. "We invite you to share your knowledge and submit an abstract within one of the scientific tracks noted.”

SLAS2013 keynote speakers include:

Mehmet Toner, Ph.D., is the Helen Andrus Benedict Professor of Biomedical Engineering at the Massachusetts General Hospital, Harvard Medical School and Harvard-MIT Division of Health Sciences and Technology. Scheduled for Monday, 14 January, Dr. Toner's presentation, "Bioengineering and Clinical Applications of the Circulating Tumor Cell Microchip,” will share his integrated strategy to simultaneously advance the engineering and microfluidics of CTC-Chip development, the biology of these rare cells and the potential clinical applications of circulating tumor cells.

Sir Harold "Harry” Kroto, Ph.D., is a Francis Eppes Professor of Chemistry at Florida State University, where he is carrying out research in nanoscience and cluster chemistry. In 1996, Dr. Kroto was one of three recipients of the Nobel Prize for Chemistry, an honor that resulted from his 1985 laboratory experiments that uncovered the existence of C60 Buckminsterfullerene, a new form of carbon. To be presented on Tuesday, 15 January, Dr. Kroto will discuss "Science and Society in the 21st Century.”

Charles Sabine is an Emmy-award-winning television journalist who witnessed wars and revolutions as a correspondent for NBC News. Today, he is a spokesperson for patients—and their families—suffering from neurodegenerative disease. At SLAS2013, Sabine will 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. His presentation, "A Perspective on Living with Huntington's Disease,” is scheduled for Wednesday, 16 January.

In addition to the scientific podium presentations and three keynote speakers, SLAS2013 includes a full slate of short courses, poster presentations, industry-sponsored tutorials and workshops, as well as an exhibition showcasing more than 325 companies from around the world.

Submit your abstract by Monday, 30 July at:

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Member Profile

ISEH, comprised of 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 2012 McCulloch and Till Award winner Timm Schroeder, Ph.D., Stem Cell Dynamics Research Unit, Helmholtz Center Munich – German Research Center for Environmental Health, Germany and this year's ISEH McCulloch and Till Award winner.

McCulloch and Till Award winner and his novel technology

Timm Schroeder, Ph.D.
Director, Stem Cell Dynamics Research Unit
Helmholtz Center Munich – German Research Center for Environmental Health
Munich, Germany

"I was always fascinated by stem cell systems, in particular of the blood system with its many cell types, complicated organization throughout the body and its immediate clinical relevance,” states Schroeder. "After working on the role ofsignaling pathways and transcription factors in controlling cell behavior for a while, I realized that the population- and snapshot-analyses that we usually use in the field are not precise enough to really understand what the cells of interest are actually doing. That kind of experiment allows very different interpretations, and I felt that this was a major reason for many of the long-standing disputes in hematopoiesis research. I therefore wanted to use time-lapse microscopy to allow the continuous long-term observation of individual cells, similar to what is routinely done in invertebrate models like C. elegans. I was, and still am, convinced that this type of read out is required for a conclusive understanding of molecular cell fate control. After wasting a lot of money and time, I realized that none of the commercially available systems were any good. The lack of suitable software was the major problem. Since I had programmed a bit in high school and university, and wasn't as afraid of tinkering around with imaging and computer hard- and software as most biologists, I decided to start developing things myself. I felt that due to my combined experience in stem cell and molecular biology, imaging and computer programming, I could contribute something unique to the field. It certainly was a risk to develop novel technology instead of just efficiently using existing approaches for obvious applications. In hindsight it was worth it, and it was a lot of fun.”

According to the Helmholtz Center website:

We have therefore developed a bioimaging system including newly developed software to allow the observation of the behavior of all cells in hematopoietic cultures over long periods of time.

Through a combination of cutting edge technology in stem cell purification and culture, transgenic animals, microscopic imaging, electronic image processing and bioinformatics, the fate decisions of hematopoietic cells can now be documented with highest resolution. This allows defining the exact effects of genes, compounds and the microenvironment on the behavior of blood cells with higher precision than classical approaches.

During Schroeder's ISEH 41st Annual Scientific Meeting presentation in Amsterdam, the McCulloch and Till Award winner will describe why he decided to develop these bioimaging approaches, and how they are used to address long-standing questions in the field.

Today, using these tools, Schroeder and his team at the Helmholtz Center Munich try to understand the molecular control of stem and progenitor cell fate decisions in health and disease.

"Quantitative single cell analyses, in particular through long-term bioimaging, are central in our approaches,” he explains. "Our own projects mostly concern hematopoiesis, but also embryonic and mesenchymal stem cells. In addition, we have many collaborators specializing in other cell systems coming by from all over the world to use our technology. It is great fun to have all those interesting people and questions come through! It is also a perfect way for the students and postdocs in the lab to see what is going on in other labs and make important personal connections.”

Schroeder says the biggest challenge facing him in his professional life today is finding excellent colleagues with a scientist's mindset for his lab. At the same time, he adds, it is also one of the most rewarding things to see students who "catch fire for science.”

Grateful to have been named the McCulloch and Till Award winner, Schroeder is a long-time ISEH enthusiast who had an unforgettable experience at the first ISEH meeting he attended.

"As a second year Ph.D. student at the meeting in Monte Carlo – in front of hundreds of experts in a plenary session – Don Metcalf asked the first question,” Schroeder remembers. "ISEH meetings are great for that kind of exposure for young students. That wouldn't happen at most other meetings. I also remember that I first met Gerald de Haan, our current ISEH president and great scientist, at a party by the beach that evening. He was starting the mouse breeding for his genetical genomics approaches then. We were in the last group that was thrown out from the place and then moved on to the Monte Carlo Casino to party a bit more! Ever since, the ISEH meetings have been ideal for meeting new and old friends to catch up and discuss new ideas.”

In addition to his time in the lab, Schroeder loves to travel to remote places and photograph nature.

"It is a great way to take my mind off things when I go to new places for novel experiences,” he shares. "I guess it is similar to what I do in the lab – use imaging to try to capture the beauty of our world and to learn. There is one big difference though. In the lab, photos have to be informative, but don't have to look nice. Outside the lab, it is just the other way around.”

You can connect with Timm Schroeder now through the ISEH member database. Click here to contact him or to build your personal profile. You can also learn more about the Helmholtz Center Munich – German Research Center for Environmental Health.


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