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Society News: February 2017

Posted By Connections Editor, Friday, February 24, 2017

Registration and Call for Abstracts now open for the 46th Annual Scientific Meeting

Join us for our 46th ISEH Annual Scientific Meeting, taking place 24-27 August 2017, at the Goethe University Frankfurt. Take advantage of group registration discounts and coordinate with your colleagues to attend the Annual Scientific Meeting together.

Submit your work for the unmatched opportunity to present at the ISEH Annual Meeting. Share your expertise in the field, through valuable speaking and networking experience.
Read more on website

 

 

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Webinar Review: The evolving view of the hematopoietic stem cell niche

Posted By Connections Editor, Wednesday, December 14, 2016

Where are stem cells found and why it matters?

ISEH Webinar review: “The evolving view of the hematopoietic stem cell niche.”

by Kena Flores

 

It has been almost 40 years since Ray Schofield postulated the existence of a stem cell niche, a specific place within the bone marrow where stem cells reside and interact with “other cell types” that regulate their physiology [1]. Schofield did not know the nature or identity of these cell types, nor the mechanisms by which they regulate the hematopoietic stem cell (HSC) physiology, but he planted the seed of a prolific research field that is now a hot topic on stem cell biology and that is relevant not only for normal hematopoiesis, but for leukemia, stem cell therapy, cell expansion, and aging, among others. To discuss the latest updates on the HSC niche, on 14 June 2016, the new investigator committee organized a webinar titled “The evolving view of the Hematopoietic Stem Cell niche”. The webinar content was didactic and appropriate for the “newbies” in this field, but also for those who have been following this field since its very beginnings. It not only recapitulated where the information about the HSC niche stands now, but it discussed the open questions, and the new directions of this research.

 

The webinar was moderated by Dr. Cristina Lo Celso, from the Imperial College London, whose research has contributed to the study of the in vivo visualization of the HSC niche. She elegantly introduced both speakers and moderated the Q&A session. The first speaker on the webinar, was Dr. Sean Morrison (Children’s Medical Research Institute, UT Southwestern), who is a researcher that has overcome several technological and conceptual challenges on this field, including defining new HSC markers and developing novel methods to elucidate the nature of the “other cell types” and their mechanisms to regulate HSC physiology. In his talk, Dr. Morrison presented an overall picture of most of his vast contributions, providing a rationale for his research. His approach has not only been to describe the location of HSC, but to elucidate which cells secrete the factors that promote HSC maintenance in the context of the bone marrow anatomy. Dr. Morrison’s group was the first to map the HSC into perivascular areas, a location that has now been validated by other researchers and that it seems to harbor most of the HSC cells.  However, there are multiple cells located into the perivascular areas, including endothelial cells, mesenchymal stromal/stem cells (MSC), and various mesenchymal progenitors and megakaryocytes, so, the nature of the cell types that regulated HSC physiology was still unresolved. To address this issue, Dr. Morrison’s group applied mouse cre technology and deleted three HSC regulators: stem cell factor (Scf), CXCL12 and Angiopoietin 1 (Angpt1) into specific populations, and found that endothelial cells and LepR+ stromal cells are the physiological sources of these HSC factors. Finally, Dr. Morrison presented his most recent papers where he developed a deep imaging and 3D reconstruction of the bone marrow and found that 95% of HSC contact LepR+ perivascular stromal cells, and he finished with the biological characterization of the LepR+ perivascular stromal cells, which are the major source of osteoblasts, adipocytes and cartilage in adult bone marrow.

 

Dr. Simon Mendez-Ferrer (Wellcome Trust-Medical Research Council, Cambridge Stem Cell Institute) provided a brief, but detailed summary of the latest findings on the HSC niche. He stated that “there is more consensus than discrepancies on the field”, a statement that was validated with Dr. Morrison’s presentation, as they both agreed that most HSC reside near blood vessels. It looked like the era of the endosteal niche (that refers to the presence of HSC in endosteal and trabecular areas) has come to an end. It has been only three years since Dr. David Scadden and Dr. Paul Frenette argued about this topic on the second ISEH Webinar.  However, Dr. Mendez-Ferrer raised the fact that endosteal areas are also highly vascular, data that might still leave the “door open” for the endosteal location of HSC within the bone marrow. Dr. Mendez-Ferrer presentation focused on the future challenges, in particular, he analyzed the existence of specific subpopulations of endothelial and perivascular stromal cells that may possess different functional properties, the presence of different niches, and the disadvantages of deleting single molecules from single niche cells that can be technical (inefficient recombination) or biological (redundancy of factors and compensation with other factors). Dr. Mendez-Ferrer finished his presentation with the description of the HSC MSC interactions in myeloproliferative neoplasms, which can be one of the reasons for “why studying the HSC niche matters”.

 

The webinar closed with a very interesting session of Q&A, in which webinar attendees had the opportunity to have an open dialogue with two of our leaders in this field. Questions about the oxygen levels within the niche, the impact of irradiation and age were addressed by both speakers. One of the topics that raised several questions was the LepR+ stromal cells. Dr. Morrison answered these questions, including questions about the heterogeneity and the possible presence of subpopulations within the LepR+ cells, the use of this marker in humans, and the “exclusivity” of the HSC niche and the fact that there are 100 times more LepR+ stromal cells than HSC.

 

We received the answers to both of our initial questions at the close of the webinar: HSC are located in perivascular areas and are regulated by endothelial and mesenchymal stromal cells, and it “matters” for many areas, including, normal hematopoiesis, aging, and hematopoietic neoplasms. Nevertheless, and after many years of research, including the research conducted by our two speakers and the moderator, it looks like we are standing at the “tip of the iceberg.”  The HSC niche still has many secrets that need to be elucidated. We are certain that this webinar will inspire you to get involved in this topic, or give you a quick insight/update into this interesting field.

 

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ISEH Renewal Season is Here!

Posted By Connections Editor, Tuesday, November 1, 2016

It's ISEH Membership Renewal season—Renew today!

To renew your membership log into your account, and pay your dues by clicking on "Renew Your Membership Now." If you are not automatically directed to this page upon your login, click here to access the renewal page. Need help with your login information? Email info@iseh.org for assistance.

ISEH Member Benefits

  • Hematology 101: Scientific education delivered directly to you through online sessions
  • Experimental Hematology:
    • Free online subscription
    • No Page Fees for articles published
    • No manuscript submission fees
  • ISEH Connections in Hematology: the ISEH electronic newsletter - the exclusive source for society, member, and industry news
  • Reduced registration fees at the ISEH Annual Scientific Meeting (up to $245 savings)
  • Free abstract submission for oral and poster presentations ($25 savings per abstract)
  • Eligibility for ISEH awards and travel grants
  • Free access to the 2017 ISEH Webinar Series
  • Two free postings per year on the ISEH Career Site, your online resource to the next career opportunity

Do you know 5+ scientists who should be members of ISEH and have been waiting for the right moment? The time has come, ISEH is offering group membership rates for groups of five or more new members from the same facility. Email info@iseh.org for more details.

 

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ISEH Board of Directors Election Results!

Posted By Connections Editor, Friday, August 19, 2016

ISEH closed its 2016 election on 11 July. In this year's election 26% of ISEH members voted. The results of the election were extremely close, which speaks to the high quality of candidates on the ballot. We would like to extend our sincere thanks to all candidates who ran this year. ISEH is fortunate to have so many dedicated members.

 

Your newly elected ISEH Board Members include:

 

 Vice President: Bertie Göttgens


 

Director, Pacific Rim: John Pimanda


 

Director, Europe: Michael Milsom


 

Director, Americas: Shannon McKinney-Freeman


Congratulations! ISEH can expect another great year with these great leaders adding their expertise to the Board.

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Review: ISEH Spring Webinar

Posted By Connections Editor, Thursday, June 16, 2016

The role of inflammatory signals in embryonic HSC development and adult HSC function

Webinar April 5th 2016

 

Marieke A.G. Essers 

Heidelberg Institute for Stem Cells and Experimental Medicine (HI-STEM) gGmbH; German Cancer Research Center (DKFZ)

Inflammation is a double-edged sword. Inflammatory signals are needed to fight infections, yet too much can contribute to hematologic diseases such as bone marrow failure and malignancy. In recent years since the discoveries from our group and the group of Peggy Goodell that the pro-inflammatory cytokines Interferonα (IFNα) and IFNγ lead to activation of quiescent hematopoietic stem cells (HSCs) in vivo, there has been a revival to uncover the role of these cytokines in the HSCs and the hematopoietic system as a whole. The most recent webinar from ISEH entitled “The Role of Inflammatory Signals in Embryonic HSC Development and Adult HSC Function” presents work exploring the role of inflammation in disease and development from leaders in the field- Markus Manz (University Hospital in Zurich), Trista North (Harvard Medical School), and moderated by Katherine King (Baylor College of Medicine). The webinar is now available for viewing online at http://www.iseh.org/?ISEHWebinars.


In general, pro-inflammatory cytokines are produced by cells of the immune system in response to an infection or inflammation. Classically, they are thought to play an important role in the defense against infection by imposing an anti-proliferative effect on differentiated hematopoietic cells, thus preventing the virus from spreading around the body. However, our study and that of the Goodell group in 2009-2010 showed that in the adult mouse, quiescent HSCs directly respond to IFNα or IFNγ, leading to increased proliferation of these cells. These data suggested that HSCs themselves are able to directly respond to infections.
In this most recent ISEH webinar, Dr. Markus Manz gave us an overview of the effect of inflammation on adult HSCs. Over the last years, the Manz lab has published several manuscripts on the direct versus indirect sensing of pathogens by HSCs and the consequences of this on HSCs. In the webinar, Manz started off describing clinical observations that systemic bacterial infections in patients can lead to a demand-adapted response, suggesting stem and progenitor cells dynamically sense and adapt to environmental signals during infection. By creating tissue-specific knock-out lines for Myd88 (a critical adapter for many inflammatory signaling pathways), they could show that endothelial cells in the BM catalyze demand-adapted granulopoiesis resulting from systemic infection in the mouse. He went on further to show that HSCs express Toll-like receptor 4 (TLR4) and can proliferate in response to the bacterial pattern recognition molecule lipopolysaccharide (LPS). Manz then presented new data using a CFSE-labeling HSC assay to assess division history to determine which clinically relevant cytokine/chemokine receptor agonists/antagonists drive HSCs into self-renewing divisions. Their data combined with work from others that depending on the type of pathogen HSCs can either directly or indirectly sense and respond to infection.

Clonal hematopoiesis with somatic mutations is a common age-related condition and inflammation increases with age. Clinical reports indicate a correlation between a history of major infections and the development of MDS/AML in patients. At the end of his presentation, Manz connected the dots and gave his perspective on how infection-induced effects on quiescent HSCs influence hematopoietic ageing and age-related disease. Future experiments testing whether severe infections affecting the quiescent HSC pool increase the risk for the development of malignancies will demonstrate if these clinical correlations are truly driving forces.
In the second half of the webinar, Dr. Trista North talked about the role of these same pro-inflammatory signals during the emergence of the first HSCs in the embryo. Trista gave us a great overview of the recently discovered new role for pro-inflammatory cytokines like IFNs and Tumor necrosis factor α (TNFα) during development. In the embryo, the first hematopoietic stem and progenitor cells (HSPCs) arise in the aorta/gonad/mesonephros (AGM) region from hemogenic endothelium. Several groups (including North, Nancy Speck, David Traver, Victor Mulero, Didier Stainier, and Feng Liu) recently demonstrated a novel function for interferons and TNFα signaling during the emergence of the first HSCs in the AGM in zebrafish and mice. They showed that key molecules involved in innate immunity and inflammation are expressed in emerging stem and progenitor cells as well as endothelial cells in the AGM region. During embryonic development, formation of primitive myeloid cells precedes the birth of definitive HSCs. Genetic ablation studies in zebrafish revealed that these primitive myeloid cells are the source of the inflammatory cytokines important for HSC emergence. North also showed new data from a screen performed in zebrafish identifying other inflammatory cytokines utilized during HSC formation. As many of the inflammatory cytokines employed during HSC emergence and the response of adult HSCs to infection are conserved, the screens from Manz and North will be mutually beneficial informing new players critical for HSCs from embryo to old age.

In summary, the data presented in this webinar by Markus Manz and Trista North showed again that there is much more to pro-inflammatory signaling in the hematopoietic system than their role in clearance of infections. Pro-inflammatory signaling plays a role in hematopoiesis from development until adulthood, from the quiescent HSC to the differentiated cells of the system. The great challenge of the future is to understand how pro-inflammatory signaling is influencing these different aspects of hematopoiesis and what the consequences are for ageing and malignancies.

 

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Society News: February 2016

Posted By Connections Editor, Thursday, February 18, 2016

Registration and Call for Abstracts now open for the 45th Annual Scientific Meeting

Join us for our 45th ISEH Annual Scientific Meeting, taking place 25-28 August 2016, at the Westin San Diego Gaslamp Quarter. Take advantage of group registration discounts and coordinate with your colleagues to attend the Annual Scientific Meeting together.

Submit your work for the unmatched opportunity to present at the ISEH Annual Meeting. Share your expertise in the field, through valuable speaking and networking experience.

Read more on website

 

Submit your T-shirt Ideas

ISEH has initiated a T-shirt design contest which is open to all members. Winners will receive $200 and 5 free shirts with their design on it. Submit your ideas today!

Deadline is 29 February 2016.

Click here for more info

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Webinar Review: “For singles only”, the new admission criteria in the hematopoietic stem cell biology field.

Posted By Connections Editor, Wednesday, December 23, 2015

Eugenia (Kena) Flores-Figueroa. Oncological Research Unit at the Mexican Institute of Social Health, Mexico City, Mexico.

  

In the last few years we have witnessed the shift from studies addressing heterogeneous hematopoietic stem cell (HSC) populations to single cell studies, which have contributed to a better understanding of the clonal heterogeneity of stem cells, the dynamics of stem/progenitor cells over time and upon inflammation, their location within the bone marrow (niche) and their hierarchy.  Technical innovations to label and track single cells, is the force reshaping stem cell biology. These new technologies might look intimidating and hard to follow for the non-expert (like me), but it is definitely a must-do for anyone on this field. To my delight, ISEH recently organized their first technology-focused webinar on this topic, “comparison of methods for cell labeling and clone tracking”, which helped me to get a better understanding of the methodologies, and also of the field as a whole. Interestingly, I had a completely different - but equally useful - experience compared to the recorded webinar; the live webinar was more interactive and I had the chance to ask a question to one of the speakers, and the recorded webinar gave me the chance to set my own pace, read the papers cited by the speakers, and reach a much deeper understanding.

Dr. David Kent, from the University of Cambridge, was the first speaker. He explained the problem faced by the stem cell biology field using an analogy from his former mentor; “If you have two handfuls of sand, one in each hand, and only one has a seed in it, in order to know which handful of sand has the seed, you will have to plant both; so you will know that the handful of sand capable of growing a plant had the seed. The problem is that if you are interested in studying the seed, after the assay the seed no longer exists, as it has become a plant, and if you study the handful of sand before you plant it, you will end up describing mostly sand and not seed”. So how can you study the molecules in a seed? In the analogy, the seed represents a HSC, and the test that helps us find out if the handful of sand is a plant, is the gold standard in the stem cell field, the transplantation of single cells into an irradiated host, followed by engraftment analysis using donor cell specific cell surface markers (like CD45). The problem with this approach is that the assay to test whether or not a cell is truly stem cell had to be measured by the progeny of the cell, thereby destroying the original cell. In this technology-focus webinar, Dr. David Kent and Dr. Leila Perié, from the Curie Institute, discuss two different approaches to overcome that problem, chaired by Dr. Claudia Waskow, from the TU Dresden.

Dr. David Kent adapted a flow cytometry technology called “Index Sorting” to integrate single cell gene expression and single cell functional data. His approach was to transcriptionally profile single cells from several cell isolation strategies (from many different groups) to identify the genes that overlapped between them with the rationale that the non-overlapping cells would represent different contaminating cells, and the overlapping genes will identify stem cells. Then he performed functional assays, and assigned individual outcomes, and coupled these data by assigning an individual outcome to each of the cells and retrospectively plotting those outcomes on a flow cytometry plot that also contained the gene expression outcomes (Wilson et al., 2015, Cell Stem Cell & Schulte et al., 2015, Exp Hematol). Using this strategy, Dr. Kent’s laboratory was able to identify a population that contains 50% of murine HSC function using the index sort data and track the markers CD150+ CD48- SCA-1 high EPCR+ that were less committed, divided slower, retained HSC markers, showed higher chimerism and robust multilineage progeny. His pioneering method has made it possible to study single cell biology and link mammalian stem cell functions with different markers and pathways. After his presentation, Dr. David Kent was approached by many interesting questions from the audience, where he discussed the limitations of his technique and recognized that there are still unanswered questions like the symmetric vs asymmetric division of HSC, where data is not conclusive; the dependence of transplantation models that still have technical challenges, like the time of engraftment read out, that have increased from  12, 16 , 24, 32 weeks, but that it may still not include rare stem cells that repopulate mouse after 6 months. Index Sorting is a technique that can be applied to any population where there is a defined single cell assay, this technique has been successful in the study of human mammary progenitor cells, but studying human HSC are still a challenge.

Dr. Leila Perié’s barcoding technique to track single cell lineages has allowed her to decipher, reshape and “trim” the hematopoietic tree to redefine the hierarchy of different progenitors (Naik S., 2013, Nature; Perié L., 2014, Cell Rep; Naik SH., 2014, Exp Hematol; Perié L., 2015 Semin Cell Dev Biol). In the webinar, Dr. Perie presented a global view of lineage tracing methods and offered a guided step-by-step list to choose the right method for each project and then focused on the barcoding technique and gave some useful examples of her discoveries using this technique. After her presentation, I had a clearer vision of where to start and which questions I should address first. The barcoding technique relies on the “insertion” of a unique sequence using a viral library (the barcode) into your cell of interest, the transplantation of those cells (on a murine system) and then tracking the barcode (usually by nested PCR and deep sequencing). Dr. Perié’s advice was to first ask ourselves if our population of interest can be transduced, this is a critical step and the biggest limitation of this techniques (for example, human and leukemic HSC are difficult to transduce); if we choose a retrovirus, we will need at least one cell division to integrate the barcode, which is not the case for a lentivirus, were we optimized the time for transduction (usually 6 hours). The diversity of the library, the size of the barcode and the sequence is another critical step, and finally the bioinformatics step, where there is no standard method.

The barcoding technique is not free of challenges like the repeated usage of the same barcode within two different cells, multiple integrations, low transduction efficiency and size of the cell expansion, among others. Dr. Leila Perié’s own work demonstrates the power of this technique, when you face those challenges, as she has contributed to the literature of tracing the fate map of LMPP, MDB and CMPs analyzing their heterogeneous outcomes , which has helped to redefined the hematopoietic tree, regarding dendritic, erythroid and myeloid cells.

The analysis of single cell biology has dramatically reshaped our field, not only addressing questions that we were not able to before, but also changing old paradigms, new and young laboratories are contributing to power this revolution, and I encourage each member of our society and a member of our field to keep up with these novel techniques; webinars are one of the tools we have to learn and to discuss these methods. There are still many unanswered questions, and I think this webinar will encourage many of our young scientists into this field. 

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Society News: January 2016

Posted By Connections Editor, Monday, December 21, 2015

It's ISEH Membership Renewal season—Renew today!

To renew your membership log into your account, and pay your dues by clicking on "Renew Your Membership Now." If you are not automatically directed to this page upon your login, click here to access the renewal page. Need help with your login information? Email info@iseh.org for assistance.

Remember, Active members can now renew for three years and then cross

"renew ISEH membership” off your to-do list for the next two years!

Active membership now includes 2 free Career Center posts every year!

Do you know 5+ scientists who should be members of ISEH and have been waiting for the right moment? The time has come, ISEH is offering group membership rates for groups of five or more new members from the same facility.

Email info@iseh.org for more details.

 

Save the Date for the 45th Annual Scientific Meeting

Westin San Diego, Gaslamp Quarter, San Diego, CA 25-28 August 2016

As you look forward to welcoming the New Year, remember to include the ISEH 44th Annual Scientific Meeting on your 2016 calendar.

Registrations opens 17 February 2016 

 

Considering submitting an abstract for 2015?

ISEH Call for Abstracts will open on 15 February 2016 


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Report of the 44th Annual ISEH Meeting - A New Investigator Perspective

Posted By Connections Editor, Friday, November 6, 2015
Contributed by Katharina Rothe, Graduate Student, Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada, and Dr. Hiroshi Kobayashi, Post-doctoral Fellow, National Institute for Global Health and Medicine, Tokyo, Japan


With its 1200-year history, Kyoto has created a unique, traditional culture that roots deeply in the mind of every Japanese. At the same time, Kyoto is a modern city where people provide excellent services and generate cutting-edge technology. The landscape of Kyoto is a colorful combination of ancient and modern architecture with more than 2000 different shrines and temples distributed throughout the city. It was in this beautiful city where the 44th annual scientific meeting of the International Society for Experimental Hematology (ISEH) convened from September 17-19, 2015. The meeting was presided by the Society’s President Dr. Paul Frenette and the Chair of the Scientific Committee Dr. David Traver. 427 participants contributed to this years exciting conference in which the support of new investigators and fostering collaborations continued to be a priority to advance the field of hematopoiesis.

Similar to the city where the meeting was held, novel technologies met long-standing questions of hematology to create a breathtaking atmosphere and an excellent exchange of ideas. The four recurring themes this year included: i) understanding the generation and expansion of hematopoietic stem cells (HSCs), ii) the role of clonal hematopoiesis in leukemogenesis, iii) the importance of the bone marrow (BM) microenvironment in both normal and malignant hematopoiesis and iv) combining novel technologies such as imaging, proteomics, genomics, and epigenomics to understand every possible aspect of hematopoiesis.

Donald Metcalf Lecture
The meeting started with the Donald Metcalf Lecture given by Dr. Elaine Dzierzak, Professor of Haematological Regeneration at the University of Edinburgh, and an outstanding pioneer in the field of developmental hematopoiesis. Dr. Dzierzak introduced her presentation by honoring seminal work in the field to identify origins of definitive hematopoiesis, and the search for colony formation units in murine embryos as carried out by Dr. Metcalf. In her early research career, Dr. Dzierzak provided definitive evidence for the aorta-gonad-mesonephros (AGM) region as the site of origin of HSCs. Pictures of her beautiful, growing garden (Dr. Dzierzak is a good gardener), served as an analogy to the excellent research blooming in her lab. Live imaging of sphere-shaped-Sca-1-GFP+ cells emerging at the embryonic aorta was truly convincing evidence for the phenomenon named endothelial-to-hematopoietic transition as well as for the existence of hemogenic endothelium. Dr. Dzierzak has further advanced our understanding of molecular mechanisms underlying HSC emergence by combining genetic ablation of essential HSC genes such as Gata2, and reporter systems like Gata2-Venus and BMP-reporter mice. The last part of her talk included a short movie of her lab members loving their research life. With this introduction, we were very much looking forward to a very enjoyable and fruitful meeting.

HSC aging and leukemogenesis
HSC fate is influenced by a number of intrinsic and external cues. As highlighted in the following 3 presentations, elucidating the underlying molecular mechanisms will help us to understand HSC aging and the development of leukemia. Dr. Margaret Goodell, an expert in stem cell biology, emphasized the importance of epigenetic regulation to balance HSC self-renewal versus differentiation. In particular, the de novo DNA methyltransferase 3a, Dnmt3a, and the demethylase Tet2 were described as key players. Dr. Goodell proposed a competition model between Dnmt3a and Tets for maintaining DNA methylation in HSCs to prevent leukemogenesis. To investigate this concept, the Goodell group generated Dnmt3a and Tet2 double knockout (DKO) mice. Interestingly, these mice displayed a high incidence of B-cell lymphoma, were anemic, had an increase in progenitor cells, and died earlier compared to wild-type mice. In addition, HSCs of these DKO mice showed a loss of methylation of regulators of differentiation, including genes that direct red blood cell development such as Klf1. These results suggest a critical role for Dnmt3a and Tet2 to balance stem and progenitor cell differentiation, but also their importance in cell transformation when both epigenetic modifiers are mutated.
Next, Dr. A. Wagers asked how environmental changes and aging affect stem cell functions. Dr. Wagers addressed this issue by investigating the systemic humoral factor GDF11 in a muscle degeneration model. Systemic elevation of GDF11 ameliorated muscle degeneration associated with aging, clearly showing that environmental factors affected stem cell aging. However, in contrast to myocytes, Dr. Wagers also demonstrated that in a heterochronic parabiosis system, “rejuvenelization” of the surrounding environment did not reverse an aged HSC phenotype. This is consistent with the previous view of HSC aging as a cell-intrinsic process. Dr. A. Hirao shed light on an intrinsic mechanism of HSC aging by focusing on Spred1, a negative regulator of Raf and c-Kit signaling. Spred1 was found to be upregulated in aged HSCs, thereby compromising the self-renewal ability of HSCs. Dr. Hirao also showed that both Spred1 and 2 inducible knockout mice tend to develop leukemia, underscoring the yin-yang of stem cell longevity and leukemogenesis. In conclusion, three presentations gave us a clue to unveil the enigma of stem cell aging and leukemia.

Targeted eradication of cancer cells by antibody therapies
Dr. Irving Weissman, a pioneer in the identification and isolation of mouse blood-forming stem cells, shared enthusiastically with us his exciting results and promise of an antibody-mediated eradication of cancer cells. CD47 was discovered as a cell surface marker of aging red blood cells in mice. However, the Weissman lab also observed that leukemic stem cells (LSC) in AML and many other cancers displayed elevated expression levels of CD47, a “don’t eat me” signal, allowing cells to evade phagocytosis. A humanized antibody, 5F9g4, has brought hope to novel targeted therapies and limiting the use of radiation or cytotoxic drugs. Phase1/2-trials are currently conducted and the antibody is filed for patent in the US. Initial dose-dependent anemia complications in mouse and rat studies were improved greatly over time with Epo gavages. The results from monkey studies seem to be promising too, and dose-escalation curves for solid tumours are on the way, and we are looking forward to seeing the data.
Another example of antibody-mediated therapies was presented by Dr. Koichi Akashi. Anti-TIM-3 antibodies have been successfully used in mice to eliminate engrafted human AML LSCs. In addition, mice with reconstituted AML or other myeloid malignancies displayed increased serum levels of human Gal-9. This suggested that Gal-9 is secreted in an autocrine manner by cancerous cells and that the TIM-3/Gal-9 pathway may play an important role in myeloid diseases, making novel therapies inevitable.

Imaging hematopoiesis
Imaging technologies have, since the development of microscopy, created an art in science and allowed us to reveal great, novel aspects of the living. Due to the surrounding marrow space, the BM is one of the most difficult places to approach by microscopy. Dr. F. Arai concisely reviewed and introduced to us recent advances in BM imaging techniques that enable observation of hematopoietic cells with higher spatio-temporal resolution. Dr. Y. Kunisaki elicited 3D confocal microscopy to see where HSCs reside in their native environment, one of the most controversial topics in the field. He found that HSCs are located close to Nestin-GFPhigh pericytes surrounding arterioles. Dr. C.P. Lin developed the video-rate two-photon microscopy to observe dynamic HSC processes. This system allowed Dr. Lin to measure hematopoietic cell transmigration through Nestin-GFPdim sinusoids, but not via arterioles, as well as live monitoring of oxygen concentrations in the BM confirming that HSCs reside in a hypoxic environment. We also learned that real-time imaging of cultured cells illuminates very different aspects of HSPCs from what is observed at a single or multiple static time points. Dr. Timm Schroeder has pioneered this field and greatly impacted our views on how HSPCs undergo mitosis and differentiation. Using two lineage-tracing systems, Gata1-mCherry and Pu.1-YFP transgenic mice, Dr. Schroeder demonstrated that the CMP fraction is composed of two distinct subpopulations. In addition, by tracking the fluorescent levels of Gata1-mCherry and Pu.1-YFP, Dr. Schroeder unequivocally showed that downregulation of Pu.1 preceded upregulation of Gata1 in cultured HSCs under differentiation-permissive conditions. Classifying cultured HSPCs into 4 different subsets based on Pu.1, IL-1 and TNF expression levels and morphometry could be used to predict cell fate long before the expression of surface markers was initiated, illustrating the power of such novel life-cell imaging techniques.

The HSC niche
A central theme of this years meeting continued to be the BM microenvironment and the regulation of HSCs and progenitor cells within their niches. Dr. T. Nagasawa presented how the transcription factor Foxc1 restricts CXCL12-abundant reticular (CAR) cells to differentiate into adipocytes, thereby maintaining HSC homeostasis. Dr. Nagasawa also showed that most CAR cells overlapped with Leptin receptor (Lepr)+ mesenchymal progenitors constituting up to 1% of whole BM cells. Thus, Dr. Nagasawa raised a remaining question in the field: How can we explain the gap between the frequency of HSC (less than 0.02 % of BM cells) and CAR cells given that CAR cells secrete HSC maintaining factors? Dr. Y. Katayama focused on the inter-organ regulation of the hematopoietic system. He started his talk with a recent publication about the osteocytic regulation of HSPC mobilization through the sympathetic nervous system. Dr. Katayama demonstrated then how high levels of vitamin D induced BM fibrosis by activating αSMA+ BM stromal cells. Dr. T. Lapidot presented how reactive oxygen species (ROS) could affect HSPC fates and mobilization. Dr. Lapidot showed that BM stromal cells scavenged mitochondria of neighboring HSC in a connexin 43-dependent manner, thereby maintaining HSC quiescence. He also deciphered the relationship between the HSPC marker EPCR and nitric oxide (NO) generation. EPCR was activated by BM stromal cell-derived anti-coagulants that restrict the generation of NO in HSCs and thus, inhibited downstream cascades that lead to mobilization of HSPCs. Dr. L. Purton spoke about comprehensive measurements of BM cell fractions including osteoblasts, adipocytes, and hematopoietic cells after cytotoxic treatment. Dr. Purton showed that adipocyte numbers increased while bone loss occurred due to the upregulation of osteoclast activity via MCP-1. Dr. Purton also found that the number of HSCs (CD150+CD48- LSK cells) returned to normal level 14 days after cytotoxic treatments, whereas MPPs (CD150-CD48- LSK cells) permanently decreased in numbers correlating with lower chimerism after whole BM transplantations into irradiated mice. Dr. Purton concluded that CD150-CD48- LSK cells contribute to hematopoiesis following BM injury.

New avenues for niche-targeted therapies
Dr. David Scadden, Co-Director of the Harvard Stem Cell Institute, used two different strategies to decipher the role of specific BM niche components. The ‘proximity principle’ was based on the analysis of immediate neighbours to HSC and progenitor cells in vivo. This approach revealed a difference for endosteal lining cells in comparison to other niche cell populations. In addition, IL-18 was discovered as a regulator of quiescence of short-term HSC and CLPs, as well as a limiting factor in cell proliferation in response to injury. The second approach, the ‘take one out strategy’ by selected depletion of a specific cell type, was utilized to delete osteocytes and osteoblasts (Ocn+ cells) and resulted in decreased numbers and function of T-cell progenitors in the marrow and thymus, and reduced thymus seeding albeit normal thymic function in vivo. Further investigations yielded that the Notch ligand DLL4 is expressed on BM Ocn+ cells and in control of T-lymphopoiesis. These two examples highlight the possibility of characterizing niche-specific compartments and open up the potential in using these strategies to direct hematopoietic outcomes.
By deleting Matn4 in mice, Dr. Marieke Essers has found that the extracellular matrix protein Matn4 is critical to the expansion of long-term HSC upon stress conditions. Dr. Ayako Nakamura-Ishizu from Dr. Suda’s group reported that CLEC-2 depletion on Mk lineages reduced the production of TPO in the BM of the mice and ultimately, disrupted quiescence and repopulation potential of HSC.

Do cancer stem cells matter?

Dr. John Dick, a pioneer and expert in the identification and characterization of cancer stem cells, posed the question whether LSC are biologically important and how intra-tumoral heterogeneity could be explained alongside the cancer stem cell model. Dr. Dick provided us in his presentation with evidence that LSC, pre-leukemic HSC and genetic subclones need to be considered for successful therapies. Expression profiling of leukemic stem cells in AML revealed a stem cell gene signature that proved to be able to predict patients’ survival across more than 1000 cancer genomes. By comparing diagnostic and relapse AML patient samples combined with phylogenetic studies, pre-leukemic cells were found to survive therapy and capable of reinitiating the disease. In other words, both diagnostic and relapse samples are polyclonal and highly related, and contribute to the complex origin of relapse. Relapse could also originate from rare pre-leukemic HSC, such as Dnmt3a-mutated HSC, that evolved before diagnosis. And lastly, evidence from xenotransplantation assays suggested that AML relapsed from a rare CD33+ subset that lacks LSCs, making us all wonder whether these cases will need different therapies.

Potential new targets and novel insights in leukemias and MDS
We also continued to hear more about leukemia, potential new targets and LSC regulation. Dr. Iannis Aifantis focussed in his presentation on the importance of cohesin complexes as tumour suppressors in vivo. Novel shRNA mouse models inducible by doxycycline revealed, in contrast to in vitro studies, that cohesin silencing led to a rapid skewing of the stem cell compartment towards myeloid lineages and epigenetic alterations, affecting the expression of critical HSC differentiation genes. Aging cohesin knockout mice also developed extramedullary hematopoiesis, progressively splenomegaly and myeloid neoplasm. Similarly, the cohesin complex was identified as one of the top hits in an independent RNAi screen for self-renewal and differentiation regulators of hematopoietic stem and progenitor cells in Dr. Larssons lab. Roman Galeev, a new investigator award recipient, reported increased engraftment levels of human cells in primary and secondary mice upon knockdown of cohesin complex components and expansion of myeloid lineages, confirming a critical role for cohesins in HSCs. Dr. C. Jamieson followed up on her previous findings that ADAR1 is important in CML. Her group was interested in determining a possible role of ADAR1 in the regulation of miRNAs. Microarray analysis revealed that cord blood cells overexpressing ADAR1 displayed a similar miRNA profile as CD34+ CML blast crisis cells did, including reduced expression of let-7 family and other miRNAs involved in self-renewal pathways. Dr. T. Ito focussed on amino acid metabolism in CML. In particular, glutamate and alanine plasma levels were found to be highly increased in blast crisis versus CP CML, and BCAT1 identified as a key player in the amino acid transamination process promoting clonogenic growth and CML cell survival. Dr. F. Ishikawa performed a global gene expression analysis in primitive CD34+CD38- AML and normal cells. HCK was found as highly upregulated in AML, and in silico screening based on the structure of HCK yielded a compound that proved to be effective in targeting AML cells from poor prognosis patients in mice.  Dr. Sabine Jurado reminded us that in some myeloid malignancies 2 oncogenic alterations are necessary for efficient cancer development and/or tumour progression. She reported that heterozygous deletions of Pax5 and JAK2 initiate and maintain BCP-ALL in mice. Dr. Cedric Tremblay’s investigations revealed that the loss of the cell cycle regulator p21 impaired the enrichment of quiescent pre-LSC and negatively affected the subsequent growth of T-ALL in a Lmo transgenic mouse model. Furthermore, pre-LSC lacking p21 were re-sensitized to radiation- and chemotherapy, suggesting new avenues for improved treatment strategies in T-ALL. Studies by Dr. D.B. Lipka showed how a combination of methyl-CpG immunoprecipitation and next-generation sequencing helped to identify two distinct subgroups and 6 methylation sites in juvenile myelomonocytic leukemia with prognostic value to predict relapse in this aggressive cancer.
Dr. E. Papapetrou developed and used a novel patient-derived iPSC model to study Del(7q)-MDS. The results confirmed that monoallelic inactivation of EZH2 was not able to fully recapitulate a MDS phenotype, suggesting that cooperation between more than one gene are necessary.

Gene Therapy and Improved Xenotransplantation Models
In a session on gene therapy, Sangamo BioSciences presented us with their newest developments and successful applications of engineered zinc finger nucleases. Genome editing by these customizable restriction enzymes could be used for correcting genetic disease mutations, to disrupt genes beneficially, and to integrate or delete larger gene segments. Emphasis was placed on the 2-finger module design that allows a more specific binding to DNA. Dr. Ute Koch deleted Dicer globally to investigate the various functions of miRNA’s in Notch-driven T-ALL. Microarray analysis revealed miR-21 as a novel and critical miRNA in the pathogenesis of T-ALL by suppressing Pdcd4. By utilizing human ES cells and GFP targeting RUNX1, Dr. E. Ng followed hematopoiesis and discovered that the early expression of HOXA cluster genes is crucial to generate definitive fetal hematopoietic cells. In another presentation given by D.R. Dou, a new investigator award recipient, medial HOXA gene cluster expression was also found to be critical for proper generation of HSCs from pluripotent cells, but HOXA genes were not activated in ESC-derived cultures on OP9-M2 stroma.  An ongoing challenge in the field has been the successful long-term engraftment of human hematopoietic cells at high numbers in mice. However, recent advances in altering and improving humanized mouse models have shown great promise as presented by Dr. C. Waskow, Dr. Markus Manz and others. Mice deficient for the Kit receptor (NSGW41 mice) continuously showed, even without irradiation, higher engraftment levels of human hematopoietic cells, including a sustained production of myeloid and erythroid cells, that were not well supported in previous xenogenic models. Dr. M. Manz started to replace mouse cytokines with their human homologs such as GM-CSF, IL-3, M-CSF, hTPO, and IL-6. With this approach, for example, CD34+ human peripheral blood cells, “low-risk” AML patient sample cells, and human melanoma cells engrafted well in cytokine transgenic mice. However, as pointed out by S. Yoshihara, we will need to be cautious to not overlook possible side-effects. Her studies have shown that NSG mice engineered to produce human stem cell factor, GM-CSF and IL-3, displayed higher human chimerism and better myeloid outputs, but also an aggressive expansion of T-cells that infiltrated liver, lungs, and spleen, anemia, and thrombocytopenia.

T-cell induction from iPS cells and thymic mesenchymal cells
Induction of T-cells in vitro is a promising technology for expanding either cytotoxic T-cells that could react with tumor specific antigens or to identify T-cells suitable for rapid recovery following BM transplantations. Dr. Zúñiga-Pflücker developed a new co-culture system to induce T-cells from human iPS cells using OP9-DL stromal cell lines. Interestingly, human-derived HSCs hardly reconstituted T-cell populations in NOG mice without co-injecting human pro-T-cells, suggesting that pro-T-cells may modify the thymic microenvironment and further investigations are needed.
J. Patenaude, a new investigator award recipient, studied and compared SCA1+ mesenchymal cells from thymus, bone, and skin to shed light on their distinctive features and post-natal role. Top hits of transcriptome analyses included macrophage function and migration pathways, apoptotic cell clearance and niche support, suggesting a MC identity.

Presidential symposium
Understanding cell metabolism and its deregulation is an old and a new problem. Both Dr. Peter Carmeliet and Dr. Hiromitsu Nakauchi presented evidence for metabolic pathways that are crucial for endothelial cells and HSCs, respectively. Motivated by targeting tumor angiogenesis to treat cancer, Dr. Carmeliet focused on tip cells and stalk cells during angiogenesis. Both cell types behaved differently in terms of metabolic regulation. Tip cells utilized the glycolytic pathway and depended in particular on the PFKFB3 protein to produce 2,6-FBP. Interestingly, genetic or pharmacological inhibition of PFKFB3 normalized aberrant angiogenesis in tumors. On the other hand, proliferating stalk and phalanx cells depended on fatty acid metabolism. Stalk cells uniquely synthesized dNTPs from carbon atoms derived from incorporated fatty acids, and inhibition of the palmitoyltransferase Cpt1a damaged stalk cells and phalanx cells. Dr. Nakauchi decided to shed light on the amino acid metabolism of HSCs. He was inspired by a classic research project by Dr. Arthur Kornberg in the 1940’s, which showed that a protein-free diet quickly resulted in severe neutropenia. Dr. Nakauchi revealed that HSC specifically required valine for their maintenance. Transplanted BM cells replenished successfully hematopoiesis without prior cytotoxic treatments upon valine depletion, suggesting that a “vacant niche” is sufficient for HSCs to lodge and survive in a transplantation setting. Dr. Shahin Rafii provided us his recent substantial progress of successfully reprogramming human endothelial cells into HSC with 4 defined factors: Fosb, Gfi1, Pu.1, and Runx1. Dr. Rafii further investigated the essential factors for HSC reprogramming expressed in endothelial-derived feeder cell lines, finding that SDF1, BMP, and Notch signaling were required, while TGF-β negatively affected transdifferentiation. Despite challenges in the reconstitution of human T-cells in immunodeficient mice, Dr. Rafii demonstrated that T-cells derived from induced HSCs were functionally intact, suggesting that this technique may be a promising new method for clinical applications.

Developmental hematopoiesis
The development of the hematopoietic system is a journey of long distance; hematopoietic stem cells travel through multiple tissues and organs with many transitional differentiation states. On two separate days, seven speakers presented the progress in this topic. Dr. U. Banerjee shared with us how proliferation and differentiation of hematopoietic progenitors are regulated by local and systemic signaling in Drosophila. Dr. Banerjee showed that an injury at a distant site activated Toll signaling in HPCs and resulted in differentiation into lamellocytes, a fly counterpart of monocytes. Dr. A. Bigas elegantly demonstrated that aortic endothelial cells of the mouse AGM region are composed of heterogenous populations with Jag1+ cells and Dll4+ cells, each of which had distinct differentiation potential. In addition, the balance between Dll4 and Jag1 played a pivotal role in the appropriate emergence of CD45+ cKit+ cells in the AGM region. Dr. T. North provided us with details about the neuro-endocrine regulation of the hematopoietic development in the zebrafish, where 5-HT activated the hypothalamic–pituitary–adrenal (HPA) axis and supported HSPC proliferation through a glucocorticoid receptor. Dr. North also mentioned that hypoxic stress, which is known to be important for mammalian HSCs, activated the same cascade. Dr. V. Chandrakanthan showed by using Pdgfra-, Mesp1-, and Wnt1-reporter systems that mesenchymal cells of mesoderm-origin, but not neural-crest-origin, were essential in supporting HSC development at the AGM region. Dr. C. Robin developed a novel technique named RNA tomography (tomo-seq) to understand comprehensive transcriptional regulation in the embryonic aorta combined with spatial information. Dr. G. Lacaud demonstrated both overlapping and unique effects of the hematopoietic regulators Gfi1 and Gfi1b as downstream targets of Runx1 on the development of HSC. Gfi1 and Gfi1b recruited a member of the CoREST complex LSD1, suggesting that Gfi1 proteins potentially repress large sets of endothelial programming governing bifurcation of endothelial and hematopoietic lineages. Dr. F. Liu identified a new regulatory molecule, miR-142a-3p, that suppressed both Irf7 and p53 and positively affected HSPC formation in the zebrafish, illuminating common regulators of inflammatory signaling and DNA damage response pathways. Finally, T. Luis elucidated a functional cell population named thymopoiesis-initiating precursors (T-IPs) as a contributing population of cells to embryonic thymopoiesis. T-IPs were found to be distinct from either adult or neonatal T-cell precursors, as T-IPs did not require Notch signaling for seeding in the thymus.

Epigenetics and Genomics
Due to the remarkable progresses in hardware and software technologies, epigenetic and genomic analyses have become widely applicable to many hematopoietic studies. Nowadays, OMICS-technologies can be linked to single cell investigations, unveiling a whole new picture of mechanisms governing stem cell fate as well as leukemogenesis. Dr. B. Göttgens has been dedicated to understand complex transcriptional networks using comprehensive methods. Dr. Göttgens revealed the transcriptional regulation of developmental hematopoiesis as well as heterogeneity of adult HSCs at single cell resolution combining intensive transcriptomic and in silico analyses. Dr. Göttgens and his colleague Judith Schütte, reconstituted a virtual transcription network of hematopoietic cells based on comprehensive experimental evidence (ChIP-seq, transgenic mice, and mutation assays) and mathematical tools such as a dynamic Bayesian model, enabling simulation of genetic modification of each transcription factor. Dr. N. Cabezas-Wallscheid performed comprehensive transcriptome, proteome, and methylome analysis of HSPCs including single-cell RNA-seq of HSCs. She identified that most purified HSCs isolated with current methods can be further classified into 3 different subpopulations with different dormancy states. Dr. M. Blewitt addressed fundamental questions about epigenetic silencing through histone modification. Contrary to previous reports, Dr. Blewitt found that H3K9 methylation by Setdb1 was indispensable for the establishment, but not for the maintenance, of X chromosome inactivation. However, histone methylation by Setdb1 played an important role in the maintenance of autosomal gene silencing. Dr. D.G. Tenen enlightened us with novel functions for the protein Sall4. Sall4, a causative gene in hepatocellular carcinoma, has been previously considered as a transcription factor. With extensive ChIP-seq and RIP-seq technology, Dr. Tenen demonstrated that Sall4 is not a DNA-binding transcription factor, but rather an RNA-binding protein, whose function remains elusive. Dr. Tenen hypothesized that Sall4 may function in the splicing machinery or poly-A addition of mRNA.

DNA damage responses
DNA damage responses reside at the crossroads of stem cell aging, BM failure, and hematological malignancy. Dr. A. D’Andrea focused his presentation on Fanconi anemia, a well-known congenital aplastic anemia with a pre-disposition to leukemia development caused by a deficiency in the DNA repair machinery to cross-link DNA. Dr. D’Andrea discovered that TGF-β signaling is hyperactivated in fibroblasts from diseased patients, and inhibition of TGF-β signaling improved HSC survival, and surprisingly even reduced DNA damage itself. Through genetic screening, Dr. A. Shimamura identified a new inherited BM failure syndrome harboring a ETV6 mutation, and a Shwachman Diamond syndrome-like disease with FAM111B mutations. Dr. Toshio Suda emphasized a novel player in the DNA damage response of HSCs, Aspp1. Aspp1 deficiency accelerated development of T-cell leukemia in p53-deficient mice, suggesting a cooperative role for Aspp1 and p53 for eliminating pre-leukemic clones.

New Investigator Award Session (post-docs)
Dr. I. Beerman presented a comparison of young and aged HSCs using single cell RNA-seq technology combined with DNA methylome analysis. Her studies revealed that aged CD150high HSCs exhibited MEP-like gene expression profiles and were distinct from CD150low HSPCs as well as young HSCs. Dr. B. Gerby performed an unbiased screening to identify small molecules targeting pre-LSC in T-cell leukemia, and found 2-ME2, a microtubule-targeting drug, specifically abrogated pre-LSC as well as the DN3 fraction of T-cells, presumably due to inhibition of Myc, Notch, and Scl. The last presenter of this session was Dr. A.V. Guitart, who talked about the regulatory mechanisms of the TCA-cycle in HSCs using fumarate hydratase 1 (Fh1) knockout mice. Fh1 deficiency resulted in a profound loss of differentiated cells in fetal livers while the number of HSCs was increased. Interestingly, despite compromised TCA-cycle activity, overexpression of Fh1 in the cytosol rescued embryonic lethality, whereas HSCs lacking mitochondrial Fh1 showed limited self-renewal capacity after transplantation. This suggests dual roles for Fh1: one in clearing cytosolic fumarate, and on the other hand being a component of the TCA-cycle.

New Investigator Career Panel and Networking
ISEH has always been a world-renowned conference with a focus on normal and diseased hematopoiesis, but also on encouraging platform for young investigators and trainees. This year the new investigator carrier panel provided us with insights on how to prepare best for a job interview to become a successful investigator at the institute of your choice. Four principal investigators with various backgrounds discussed this topic with us. Dr. M. Goodell emphasized the importance of understanding and conveying well your potential as a new colleague by stating what you can bring, what you want to do, and what the lab wants you to do, in addition to what you have done. Dr. Nagasawa valued previous, published work as your door to connect to a new field or specialized area in science. He mentioned how his discovery of CXCL12 helped him to pursue his current research investigating the HSC niche. Dr. Geiger has two labs, one in Europe and one in the US. He compared cultural differences and expectations of institutions in these two regions. Finally, Dr. Lucas, a new investigator, offered detailed strategies to prepare for job interview. Common themes included: quality of the research, fit to the institution, and survival potential of the applicant as determinants to succeed.
The meeting also provided plenty of opportunities for networking, including two great poster sessions on two evenings, a Welcome Reception during the first night, a ‘Meet the Expert Mixer’ during the second evening, and an exciting annual social event during the last night with great food, music and dance. We shared precious experiences and learned from the experts not only more details about their science, but also how they live as a researcher in various countries.


McCulloch and Till Lecture
This year’s McCulloch and Till Prize was awarded to Prof. Andreas Trumpp, Division Head of Stem Cells and Cancer at the German Cancer Research Center and Founding Director of HI-STEM in Heidelberg in Germany, for his outstanding insights into the regulation of HSC features and c-Myc.
Dr. Trumpp started his presentation with an overview of his impressive career and highlights of his accomplishments in deciphering HSC and multipotent progenitor cell characteristics. Of particular interest to Dr. Trumpp were HSC dormancy and the various roles of c-Myc, a proto-oncogene that is essential to many cell processes. Interestingly, c-Myc expression is very low in quiescent HSC, but continuously elevated during HSC differentiation and deregulated in many hematopoietic malignancies, suggesting a crucial role for its precise regulation. Dr. Trumpp’s group identified a previously unknown super-enhancer element 1.7Mb away from the coding region of c-Myc in hematopoietic tissues. Functional studies indicated that it is this element that affects c-Myc expression in HSC and progenitor cells. In addition, the super-enhancer may determine tissue specificity in combination with various transcription factors that bind to the 9 modules within this element. This example illustrates very well that, in an era of extensive sequencing, integrative approaches and a wide perspective should not be forgotten to allow us to fully understand biological phenomena.

On behalf of all attendees of the ISEH 44th Annual Meeting, we extend our sincere thanks to Dr. Paul Frenette, Dr. David Traver, and the entire organizing committee for a very well executed conference. We are looking forward to meeting our fellow colleagues and collaborators in San Diego next year!

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Dangerous definitions – what is pre-leukemia?

Posted By Connections Editor, Monday, August 31, 2015
Updated: Tuesday, August 25, 2015

David Kent, University of Cambridge WT/MRC Stem Cell Institute 

 

Earlier this month, ISEH posted its 7th webinar entitled “Clonal Evolution of Pre-Leukemic HSCs in AML”. Webinars are a funny thing – we are so used to “seeing” the speaker, observing their reaction to questions, seeing the excitement (or lack of it!) for particular ideas, etc, and a webinar strips all of this away. I admit that I was skeptical when ISEH pitched the idea of webinars, but this particular webinar really opened my eyes to the value of this mode of communication.

I’ve seen Ross Levine several times before and emerged thinking “Wow, now that was a lot of data” and “I wish I could write faster”. However, in the webinar format, Ross seemed like he was sat in his office sipping a glass of wine – he was extremely relaxed and well-paced, I could even hit pause and rewind. In fact, I think Ross delivered one of the first lectures that I’ve heard in science where I did not really need slides to follow - a real treat.

Importantly, these webinars become an excellent resource for those that have yet to see talks from these researchers. It is a wonderful way to share science across the world and extend the live academic discussion beyond the boundaries of conference sessions.

However, the question and answer period was by far the best aspect of the webinar format because it captures the spontaneous and unplanned responses – where real academic discussion can occur. I thought that Ann Mullally did a brilliant job as moderator – she’d clearly done her homework and prepared some really tough philosophical questions for Drs. Levine and Majeti. She also adapted to the Q/A from other listeners, posing really interesting additional questions and giving context to those questions – a real model for how to moderate these webinars. Framing a question about where MDS fit in the pre-leukemic context, Ann made Ross and Ravi engage on the term itself. The exchange underscored for me the danger in perpetuating terms that are not accurate and Ross captured it perfectly:

“I’m gonna make Ravi respond to me – I think pre-leukemia is not the right term here. Pre-leukemia implies a likely certain probabilistic progression to leukemia and most of these people will never do that…. Most people stay there… for every one that gets leukemia, 15 are just gonna hang out.” Ross continued saying “terms: scientifically don’t mean that much, but clinically… it could mean a whole lot”

This highlighted the very important point that clinicians confused by the term “pre-leukemia” could deliver some very poor advice to their patients and raise unnecessary worries. Ross suggests that we need to engage with the idea of probabilities of progression and not use the term irresponsibly. Overall, I would say that Ravi agreed that the term shouldn’t be used for elderly patients who have a clonally dominant mutation in an epigenetic regulator, suggesting that the term should not be applied to people who simply have a clonal expansion.

However the point from Ross stands and I hear many people continue to use the term pre-leukemia irresponsibly, making the waters very murky for the non-aficionado. As a community we need to be careful about terms and their potential implications and I think having three clinician scientists argue the term really highlighted the need to get this right in the clinic.

A related question from Ann was what the therapeutic implications of leukemic complexity were - Ross took this question on and identified three main concepts that we need to master as a community. First, we need to “believe in combinations” to try and tackle the complexity. Second, we need to understand the convergence of different mutational mechanisms and whether they are therapeutically tractable. Third, the data so far suggest that we need to limit the ability of the leukemic cell to sample different states (e.g., to prevent it from evolving).

Ann also queried whether either Ravi or Ross could imagine a situation where clinicians might treat people with suspected “pre-leukemia”. Ross’ answer was fairly blunt - “not any time soon” citing the toxicity tradeoff as being too high at present. Ravi suggested clinicians would need to understand which patients would progress and any therapy would need to be done in a way that’s safe.

Overall – this is a webinar that is definitely worth your time, I hope you’ll take the time to have a listen, I certainly enjoyed it.

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