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February 2012 ISEH Newsletter
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Connections in Hematology & Stem Cells is supported by a grant from

In the February 2012 issue

Annual Scientific Meeting
Call for abstracts opens 24 February.

Experimental Hematology

Explore key manuscripts in the February and March issues.

New Investigators

2012 plans include input to scientific program speakers.

Society News
Be a part of something big. 

Member Profile
Meet Atsushi Iwama, M.D., Ph.D., ISEH 41st Annual Scientific Meeting speaker.

Annual Scientific Meeting

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

It's Time! Call for Abstracts Open Later this Month

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 opens 24 February and will remain open until 20 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.

Complete instructions will be issued via e-mail and posted at on 24 February. 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. If you have not already renewed your dues for 2012, click here. Do you want to join ISEH? Contact

If you are submitting an abstract and you are a student or Ph.D. fellow, you also may be eligible for a travel grant. Travel grants will be awarded as a component of the scientific abstract review process and will be considered on the basis of scientific merit. Travel grant requests must be submitted with the abstract submission and no later than 29 April to be considered. 

From 10 June to 8 July, ISEH will accept late breaking abstract submissions.

Take a look at the roster of invited speakers, and be sure your calendar is marked for this leading meeting for those in the exciting field of hematology and stem cell research.

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Experimental Hematology

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

In this Issue – February 2012

A potential prognostic marker; ALDHbr cells in acute myeloid leukemia 
Ran et al 
Acute myeloid leukemia (AML) is a genetically heterogeneous disease. Even though significant diagnostic and therapeutic advances have been made in the field, only 45% of the patients can be cured. Additional diagnostic and prognostic tools that will help for risk stratification and appropriate targeted therapies are highly desirable. The existence of leukemia stem cells (LSCs) was first documented in AML using xenotransplant assays. There is growing interest in the field to prospectively isolate LSCs and to define their biologic and clinical significance, and maybe to use LSC properties as prognostic tools. Several groups have documented that LSCs from patients with AML are very heterogeneous and can be enriched by high aldehyde dehydrogenase (ALDH) activity. Moreover, high percentage of ALDHbright cells (>0.36%) in the bone marrow at the time of initial diagnosis is often associated with adverse cytogenetic abnormalities and correlated significantly with poor clinical outcomes. In this study, Ran et al showed that the frequency of ALDHbright cells at diagnosis predicted the failure to achieve complete remission at the end of the first cycle of chemotherapy, and was the strongest prognostic marker affecting overall survival in the multivariate model. Moreover, ALDH activity in patients with genetic intermediate risk factors (IRG) was found to be a novel prognostic marker, as it identified those with poor outcomes. These encouraging findings should be further validated in larger cohorts of patients, and future studies should also address whether ALDH plays a functional role in chemoresistance, as it may be a potential therapeutic target to LSCs.

Clues to chemoresistance in Mantel Cell Lymphoma
Jung et al  
Mantle cell lymphoma (MCL), a subtype of B-cell non-Hodgkin's lymphoma, has a chemoresistant nature, and thus a very poor prognosis with a median survival of less than 3 years. To overcome chemoresistance in MCL and other malignancies, a better understanding of the cellular composition of these tumors is necessary. In their recent reported work, the authors of this manuscript had identified a small population of stem-like cells (CD45+19-) in MCL. These mantle cell lymphoma-initiating cells (MCL-ICs) were highly tumorigenic and had self-renewing properties in vivo, unlike the CD45+19+ cells which constituted the bulk of the tumor. The authors speculated that these cells were responsible for chemoresistance in MCL. Bortezomib (Velcade; BTZ), a selective inhibitor of the 26S proteasome, is currently the only treatment option for patients with relapsed or refractory MCL. BTZ displays its growth inhibitory and apoptotic effects in part by inhibiting proteasomal degradation of ubiquitinated nuclear factor kB (NF-kB) inhibitor. In the present study, Jung et al shed light into the limited efficacy of BTZ in patients with MCL. They show that the MCL-ICs have constitutive upregulated NF-kB signaling that they relied on for survival and that was responsible for BTZ resistance, suggesting that therapeutic strategies targeting alternate pathways are required for MCL patients. In a recent report published in Leukemia Research in October 2011, Sun et al documented a superior anti-MCL activity in vivo when BTZ was combined with Atiprimod (ATI, an azaspirane cationic amphiphilic compound with anti inflammatory and anticancer properties); mice with tumor xenografts showed delayed tumor growth and improved survival when compared to the groups that were treated with the single agents alone. The success of novel agents or directed therapies in oncology will depend on the availability of studies like this one, which dissect the phenotypic and genotypic architecture of the tumor tissue. Despite the ongoing controversies in the cancer stem cell hypothesis, such studies support their presence.

Homeostasis of hematopoietic stem cells; the role of Lnk/Sh2b3 and Bcl-xL 
Suzuki et al
Lymphocyte adaptor protein (Lnk, also known as Sh2b3) is a negative regulator of thrombopoietin (TPO)-MPL and erythropoietin (EPO)-EPO receptor-mediated JAK2 activation. Its role in regulating HSC numbers in hemostasis and in the molecular pathogenesis of myeloproliferative diseases (MPD) is now well documented in mice lacking Lnk, as well as in patients with MPD harboring Lnk/Sh2b3 mutations. In Lnk-/- mice, both the absolute number of HSCs and their self-renewal capacity were increased. Lnk-/- HSCs displayed potentiated activation of JAK2, specifically in response to TPO, which is probably responsible for the development of MPDs in these mice. In this study, Suzuki et al provided further evidence that the enhanced survival of HSCs, documented with the loss of Lnk/Sh2b3 function, was due to the upregulated expression of Bcl-xL, functioning downstream of the JAK2-STAT5 signaling pathway, which resulted in inhibition of apoptosis. The definitive role of Bcl-xL in this process was confirmed by the normalization of the repopulating ability of Lnk-/- HSCs upon shRNA mediated downregulation of Bcl-xL in these cells. This reduced apoptosis as a result of enhanced Bcl-xL expression, which is further enhanced upon TPO stimulation, may also play a role in the development of MPD in patients with Lnk/Sh2b3 mutations. Identifying the relationship between Lnk/Sh2b3 and Bcl-xL may prove useful to develop strategies to augment engraftment of HSCs/HPCs, as well as to provide new insights into the pathogenesis of MPDs and could help in the development of new therapeutic approaches.

In this Issue – March 2012

A novel agent in the treatment of progenitor B-cell acute lymphoblastic leukemia (pre-B ALL): Para-NO-aspirin 
Khan et al
Novel agents are always needed for relapsed patients with pre-B ALL. One of the nitric oxide-donating nonsteroidal anti-inflammatory drugs, para-NO-aspirin (para-NO-ASA), is several hundred fold more potent than aspirin and has anticancer properties against a number of solid tumors and chronic lymphocytic leukemia. Its anticancer efficacy is potentially mediated by the modulation of multiple signaling pathways, such as b-catenin/Wnt, MAPK and NF-kB. In this study, Khan et al showed that para-NO-ASA induced cell death in pre-B ALL cell lines by generating reactive oxygen species which resulted in inhibition of constitutively active NF-kB activity, probably via the depletion of cellular glutathione. If these exciting findings are further validated and Para-NO-aspirin's safety is documented in preclinical models of pre-B ALL, this new agent would hold promise as a novel drug that can be combined with conventional chemotherapy for patients with pre-B ALL after relapse, or for those with refractory disease.

A new transgenic mouse model of fatal B-cell neoplasia 
Linden et al
Multiple myeloma (MM) is a B-cell neoplasm characterized by malignant proliferation of plasma cells in the bone marrow, and has limited treatmant options, thus novel therapeutic agents to improve outcome in these patients are urgently needed. Animal models provide valuable tools for understanding basic biological processes and for preclinical testing of novel therapeutic agents. Recent work has demonstrated that targeted transgenic co-expression of Bcl-XL and c-myc resulted in B- and plasma cell neoplasms. Activating ras mutations involving K- and N-ras has been described in 23% to 100% of MM patients and 50% of human myeloma cell lines, suggesting that these mutations are involved in myeloma progression. In this study, Linden et al characterized the role of activated mutant N-ras in B and plasma cells in transgenic mice, and showed that overexpression of activating N-ras induced B- and plasma cell lymphoproliferation and immunoglobulinemia in aged mice. Activated N-Ras in cooperation with c-Myc induced fatal B-cell but not plasma cell neoplasia, suggesting that in a c-myc-driven murine model of MM activating ras mutations act as secondary mutations. These transgenic models are promising new tools for the field; they could be used to test efficacy of novel agents targeting N-ras and/or c-Myc and to screen small molecule inhibitors of c-Myc and activating ras protein in malignant B-cell neoplasms.

P53 mediates hematopoietic defects in rps29 mutant zebrafish 
Taylor et al
Patients with Diamond Blackfan Anemia (DBA) have red cell aplasia and craniofacial anomalies, and may develop bone marrow failure due to hematopoietic stem cell defects. Heterozygous mutations in ribosomal protein genes, such as RPS19, RPS24, RPS17, RPL35A RPL5, RPL11,RPS7, RPS10 and RPS26, are seen in more than 50% of these patients. The ribosomal protein RPS29 is part of the 40s small subunit of the ribosome, plays an important role for ribosomal RNA processing and ribosome biogenesis. In their previous work, these investigators documented that zebrafish embryos with mutations in rps29 had decreased hematopoietic stem cells. In this study, Taylor et al demonstrated red blood cell defect (decreased hemoglobin levels) and increased apoptosis in the head of these rps29-/-embryos. Both hematopoietic and morphological phenotypes were almost completely rescued upon p53 mutation, suggesting that p53 is a key mediator of the rps29 mutant phenotype. Future studies in zebrafish embryos identifying novel pathways using in vivo chemical and genetic screens may provide insights into why mutations in ribosomal protein genes so specifically affect eryhropoiesis in DBA, and may help implement novel therapeutics.

A novel non-human primate cord blood transplantation model
Watts et al
Large animal models are superior to murine models for preclinical validation of gene therapy and stem cell expansion protocols. Indeed, findings documented in these models better predict outcome from clinical trial; however, their high cost limits their wider use. There is an urgent need for the development of an efficient stem cell expansion methodology that could facilitate the use of cord blood stem cells for a broader patient population. In this study, Watts et al established a large animal cord blood transplantation model in which pig-tailed macaques were co-transplanted with autologous cord blood stem cells: half of the cells were transduced with a control vector and the other half tranduced with HOXB4 and expanded for 6 days. They showed that HOXB4 stimulated expansion and engraftment of short term repopulating cells to clinically relevant doses as previously documented using autologous mobilized bone marrow hematopoietic stem cells. Such a model is unique; it will allow comparison of different stem cell expansion methodologies in a single animal. More investigators should take advantage of this sytem for developing and testing stem cell expansion strategies that hold promise to improve outcome in clinical cord blood transplantation.

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 

Committee Secures Speaker for 41st Annual Scientific Meeting

On its monthly teleconferences, the New Investigators Committee tossed around ideas on how they could bring additional value to ISEH as an organization as well as to the Annual Scientific Meeting.

"For many years, the New Investigator Committee had been asked to help create programming for the graduate student or post-doc who might be attending the ISEH scientific meetings,” expresses Shannon McKinney-Freeman, committee chair from the Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, USA. "We wanted to do more this year than the usual career planning session and meet the professor breakfast. Therefore, we approached Scientific Program Committee Chair Elaine Dzierzak with an idea.
That idea was to be sure a newly established independent researcher was a part of the main platform. Having studied in-depth the evaluations from the previous meeting, and understanding well that the Annual Scientific Meeting is the usual way scientists first participate in ISEH, the committee felt someone on his or her own for less than four years was likely to be a big draw for investigators – in all stages of their careers – that are not yet aware of the quality interaction that occurs at ISEH meetings.

"Elaine was receptive to the idea, and our committee researched possible candidates that would bring new and exciting ideas of interest to all attendees,” McKinney-Freeman adds. "Derrick Rossi's name rose to the top of the list based on the exciting work he was doing regarding stem cell aging and induced pluripotent stem cells (iPSCs).”

Rossi, Ph.D., is with the Harvard Stem Cell Institute, USA. In his November 2010 paper in Cell Stem Cell titled, "Highly Efficient Reprogramming to Pluripotency and Directed Differentiation of Human Cells with Synthetic Modified mRNA,” his team reports on novel ways to reprogram differentiated cells to pluripotency. The introduction in that manuscript concludes:

"Here we demonstrate that repeated administration of synthetic messenger RNAs incorporating modifications designed to bypass innate antiviral responses can reprogram differentiated human cells to pluripotency with conversion efficiencies and kinetics substantially superior to established viral protocols. Furthermore, this simple, nonmutagenic, and highly controllable technology is applicable to a range of tissue-engineering tasks, exemplified here by RNA-mediated directed differentiation of RNA-iPSCs (RiPSCs) to terminally differentiated myogenic cells.”

"Derrick Rossi and his work, while certainly drawing interest from the established ISEH attendee, is likely to be of interest to a broad range of hematology and stem cell scientists and provide them with a great reason to attend the ISEH meeting in August,” McKinney-Freeman acknowledges. "Once there, they will see the quality level of presentations we offer and like many before, be totally impressed by the ability to interact so comfortably and openly with other attendees. That is, and has been, the hallmark of ISEH Annual Scientific Meetings for many years.”

For more on Derrick Rossi and his lab, click here. 

Also in the Works

McKinney-Freeman indicates that the committee has rebuilt itself a bit to ensure it is involving representatives from different parts of the world, as well as different stages of careers. New to the committee this year are Sarah Ellis from Australia, Michael Milsom from Germany and Eugenia Flores from Mexico. Each has enthusiastically participated in their monthly conference calls and taken on aspects of committee planning.

Watch for reports on additional Annual Scientific Meeting activities, career development efforts and committee formalization of goals and purpose.

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Society 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, 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!

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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. This issue, meet 2012 Annual Scientific Meeting speaker Atsushi Iwama, M.D., Ph.D., Chiba University, Japan.

Speaker Focuses on Polycomb Group Functions

Atsushi Iwama, M.D., Ph.D. 
Professor, Department of Cellular and Molecular Medicine 
Graduate School of Medicine
Chiba University
Chiba-shi, Japan 

Passionate about his work, 2012 Annual Scientific Meeting speaker Atsushi Iwama, M.D., Ph.D., looks forward to presenting in Amsterdam this summer. Iwama's presentation falls under the Epigenetics topic; Conny Bonifer, University of Birmingham, United Kingdom, also has been announced as a speaker for this topic. 

"For 10 years, I have been working on the role of polycomb genes in the self-renewal and differentiation of hematopoietic stem cells,” Iwama states. "I was very excited at the recent findings on loss of function mutations in polycomb genes. So, I started several projects focusing on how dysfunction of polycomb proteins results in hematological malignancies. In 2010, loss of function mutations of the polycomb gene EZH2 were reported regarding myelodysplastic syndrome and myeloproliferative neoplasms, proposing a tumor suppressor function of EZH2. At that time, we had been working on polycomb genes as oncogenes, but at the same time, we had some data showing tumor suppressor function of polycomb genes in our mouse model. So, our findings matched the EZH2 mutation in human disease.

"During my 2012 ISEH presentation, I will focus how the polycomb group functions in HSCs and hematological malignancies. Although our findings are based on the data from mouse models, I'd like to provide information that helps with the understanding of human hematopoietic malignancies with deregulated polycomb functions.”

Iwama began his professional journey when as a junior resident in the department of internal medicine, he became fascinated by clinical hematology.

"After training in clinical hematology, I found that basic research on hematology also fits me,” Iwama explains. "My passion for this new field in experimental hematology continues.”

Iwama currently is a professor of the Department of Cellular and Molecular Medicine, Graduate School of Medicine, Chiba University. He obtained his M.D. and Ph.D. in 1987 and 1996, respectively. Originally starting his training in clinical hematology, he has specialized in molecular biology, particularly research on transcription factors and, more recently, polycomb group genes and epigenetics, in conjunction with normal and leukemic hematopoiesis. His current major interest is the regulation of histone modification and its subsequent effects on gene expression, and eventual cell fate decision in the hematopoietic compartment. He has nurtured and grown his laboratory since he became independent as a full professor in 2005. Actively publishing papers in top-ranked journals, he desires to accomplish highly original research along with the young fellows joining his lab.

His most recent publication, in press, is "Lethal myelofibrosis induced by Bmi1-deficient hematopoietic cells unveils a tumor suppressor function of the polycomb group genes” for the Journal of Experimental Medicine. Other recent publications include "Dependency on the polycomb protein Ezh2 distinguishes fetal from adult hematopoietic stem cells,” Blood 118, 6553-6561, 2011; and "Poised lineage specification in multipotent hematopoietic stem and progenitor cells by the polycomb protein Bmi1,” Cell Stem Cell 6, 279-286, 2010.

Iwama values his ISEH affiliation and currently serves on the ISEH Editorial Board and Publications Committee. In addition to the opportunities to share great science, Iwama says that ISEH offers him the opportunity to have a "reunion with familiar faces and to get acquainted with new faces.” He knows he can turn to his ISEH colleagues as needed when faced with scientific issues with which they may have experience.

"I'm struggling to combine stem cell biology with comprehensive epigenetic analysis,” he offers. "Comprehensive epigenetic analysis requires a lot of DNA and RNA, and the paucity of stem cells really troubles me. To obtain enough materials from hematopoietic stem cells, we need a large number of mice. So, in many cases, it's not practical. But, my interest is in the epigenetic regulation in hematopoietic stem cells, which is very rare in bone marrow.”

He is deeply involved in his work, which doesn't allow much time for activities he enjoys like socializing with friends, traveling with his family, swimming, playing golf and reading books.

"Because science occupies the biggest part of my time now, I worry about my future after retirement…,” he admits.

You can connect with Atsushi Iwama now through the ISEH member database. Click here to contact him or to build your personal profile. You can also learn more about the Chiba University Graduate School of Medicine..



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