American Society of Hematology

Scientific Program

The following information is preliminary and subject to change.

The Scientific Program will be held Saturday, December 1, and Sunday, December 2, with each session being offered twice. A question-and-answer period will occur at the end of each individual speaker presentation.

Invited abstracts of these sessions will be available in the annual meeting app and in the online meeting planner.

2018 Scientific Program Co-Chairs

John Crispino, PhD

John Crispino, PhD
Northwestern University, Chicago, IL

Martha Sola-Visner, MD

Martha Sola-Visner, MD
Boston Children's Hospital, Boston, MA

Ad Hoc Scientific Committee on Epigenetics and Genomics

Epigenetic and Genomic Determinants in Cancer Immunotherapy

Immunotherapy has become one of the most promising strategies to fight cancer. Many patients treated with immunotherapy are experiencing durable remissions of otherwise treatment-refractory cancers. However, the majority of patients treated with immunotherapy do not achieve long-term disease control, and it is not clear why some patients respond well to immunotherapy whereas others derive limited clinical benefit from these treatments. This session will focus on the latest research in the field of T-cell exhaustion and immune activation in immune checkpoint therapy. It will also address the identification of novel mechanisms of resistance to genetically engineered antigen-specific T-cell therapies.

Dr. Nicholas Haining will discuss the role of epigenetics in T-cell exhaustion. T-cell dysfunction in the tumor microenvironment (TME) is a hallmark of many cancers, and reinvigoration of T-cell function by PD-1 checkpoint blockade has resulted in striking clinical responses. However, checkpoint inhibitors are effective in only a minority of patients. The basis for T-cell dysfunction in the TME, as well as the mechanisms by which anti-PD-1 therapy acts on dysfunctional T cells, are not fully understood. Dr. Haining will present new transcriptional and epigenetic studies of T cells from mouse models and patients with chronic viral infections cancer. His presentation will show that exhaustion is not simply a transient inhibition of otherwise functional cells, but instead represents a distinct and stable state of T-cell differentiation in which sub-populations of exhausted CD8 T cells have radically different roles in the immune response to cancer.

Dr. Robert Schreiber will discuss the use of complementary forms of high-dimensional genomic profiling to define the key molecular and cellular changes that occur in tumor-infiltrating immune cells upon treatment with immune checkpoint blockade. Unbiased assessment of gene and protein expression in tumor-infiltrating cells by single cell RNAseq and mass cytometry has identified common and distinct alterations induced by different immune checkpoint blockade treatments. Dr. Schreiber will address novel and unexpectedly complex changes within the myeloid compartment that prove new insights into the mechanism of action of immune checkpoint blockade therapy.

Dr. Andrei Thomas-Tikhonenko will discuss novel mechanisms of resistance to CD19-directed immunotherapies and how these resistance mechanisms may be counteracted. Significant gains have been made in the treatment of relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) through the use of CD19-directed immunotherapies (CAR-T cells, bi-specific T-cell engagers, etc.). However, relapses occur in 10-20 percent of patients with B-ALL treated with CD19 CAR T cells, often due to epitope loss. Dr. Thomas-Tikhonenko previously reported that, at least in some cases, epitope loss is achieved through alternative splicing of CD19 transcripts. He will discuss new data that highlights an additional mechanism of epitope loss wherein somatic mutations cause retention of mutant proteins in the endoplasmic reticulum. Given that this resistance mechanism frequently generates neo-antigens, it may be possible to exploit it therapeutically.

Chair:

Julie-Aurore Losman, MD, PhD
Dana-Farber Cancer Institute
Boston, MA

Speakers:

W. Nicholas Haining, BM, BCh
Dana-Farber Cancer Inst.
Boston, MA
Chromatin State and Immunotherapy

Robert D. Schreiber, PhD
Washington University School of Medicine in St. Louis
St. Louis, MO
Neoepitope Discovery

Andrei Thomas-Tikhonenko, PhD
Children's Hospital of Philadelphia, University of Pennsylvania
Philadelphia, PA
The Impact of Immunotherapy on Tumor Evolution

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Joint Session: Scientific Committee on Hematopathology & Clinical Laboratory Hematology and Scientific Committee on Myeloid Neoplasia

Metabolism and Hematologic Malignancies

Metabolism is increasingly being identified as a key factor in the pathogenesis of hematologic malignancies. This session will focus on the latest research in the field of oncometabolites, amino acids, mitochondrial dysfunction, and Myc as they relate to both disease development and novel therapeutic approaches.

Dr. Tak Mak will discuss the roles of mutations of isocitrate dehydrogenase (IDH) and the methyl dioxygenase ten-eleven translocation-2 (TET2) in acute myeloid leukemia (AML) and angioimmunoblastic T-cell lymphoma (AITL). Although it is now clear that IDH1, IDH2, and TET2 mutations drive hematopoietic tumorigenesis by interfering with cellular differentiation, the specific underlying mechanisms are still not fully understood. Genetically engineered mouse models of these single mutations, or in combination with clinically meaningful secondary mutations, including FLT3 and NPM1, have achieved models that more accurately recapitulate human AML or AITL. These models have been used to explore the hypothesis that these mutations alter the epigenetic regulation of key genes that govern hematopoietic differentiation, as revealed from single cell RNA-seq. Moreover, these models have been used to determine if clinically active mutant IDH1/2 alone, or in combination with other compounds, can mitigate AML or AITL disease.

Dr. Marina Konopleva will focus on the contribution of amino acid metabolism to hematologic malignancies. Tumor cells rewire metabolic pathways in an attempt to meet increasing metabolic rates and proliferation, and frequently rely on extracellular pools of amino acids to satisfy protein biosynthesis. Dr. Konopleva will review amino acid deprivation strategies in hematologic malignancies using heterologous or engineered enzymes with a focus on asparagine, glutamine, arginine, and cysteine starvation. Furthermore, she will discuss the role of the tumor microenvironment in amino acid metabolism and chemoresistance, as well as aspects of amino acid metabolism within the immunosuppressive tumor microenvironment.

Dr. Aaron Schimmer will review mitochondrial dysfunction in normal and malignant hematopoiesis. AML cells and stem cells have an increased reliance on oxidative phosphorylation. Mechanisms underlying this unique metabolic vulnerability in AML will be discussed with a focus on increased flux of metabolites into the tricarboxylic acid cycle (Krebs cycle) and decreased spare reserve capacity of the respiratory chain in AML cells and stem cells. Potential therapeutic strategies that can target oxidative phosphorylation will be highlighted, including respiratory chain complex inhibitors, inhibitors of mitochondrial protein translation, and the inhibitors and hyperactivators of mitochondrial protease caseinolytic peptidase P.

Dr. Stefano Casola will discuss Myc and the Warburg effect using mouse models of Myc-driven B-cell lymphomas. The effects of acute genetic inactivation of the B cell antigen receptor (BCR) on the in vitro and in vivo growth of B-cell lymphomas will be reviewed. BCR inactivation does not prevent malignant B cells from growing in vitro and disseminating in vivo; instead, the BCR provides a competitive advantage to Myc-transformed B cells. Dr. Casola will also highlight how exploiting quantitative metabolomics, genomics, and transcriptomics analyses coupled with functional genetics assays targeting candidate genes with CRISPR/Cas9 technology has helped elucidate the molecular networks that sustain competitive fitness of Myc transformed malignant B cells.

Co-Chairs:

Ravi Majeti, MD, PhD
Stanford University School of Medicine
Stanford, CA

Inga Hofmann, MD
University of Wisconsin-Madison School of Medicine and Public Health
Madison, WI

Speakers:

Tak Mak, PhD, DSc
Princess Margaret Cancer Center
Toronto, ON, Canada
Metabolic Dysregulation in Normal and Malignant Hematopoiesis

Marina Y. Konopleva, MD, PhD
The University of Texas MD Anderson Cancer Center
Houston, TX
Contribution of Amino Acid Metabolism to Hematologic Malignancies

Aaron Schimmer, MD, PhD
Princess Margaret Hospital, University of Toronto
Toronto, ON, Canada
Mitochondrial Dysfunction in Normal and Malignant Hematopoiesis

Stefano Casola, MD, PhD
FIRC Institute of Molecular Oncology Foundation
Milan, Italy
Myc and the Warburg Effect

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Joint Session: Scientific Committee on Immunology & Host Defense and Scientific Committee on Transplantation Biology and Cellular Therapies

The Making of Memory

The development of immunologic memory is critical for host defense against pathogens and for anti-cancer immunity, be it spontaneous or induced by check-point blockade or adoptive cell therapies. Although the concept of immunologic memory is old, very recent research has revealed new types of memory cells and layers of complex transcriptional and metabolic control, all of which could also be manipulated in the clinic. This session will focus on the latest research pertaining to the biology of tissue-resident memory T cells, transcriptional control and metabolic regulation of memory T cells, and the biology of memory-like natural killer (NK) cells.

Dr. Thomas Kupper will discuss the biology of tissue-resident memory T cells (TRM), which reside principally in peripheral non-lymphoid barrier tissues that interface with the environment. accumulate in these tissues as a function of time and their primary role is to mediate rapid and specific host defense. Infections in non-barrier tissues (e.g., kidney, brain, pancreas) can also lead to the recruitment of T cells, and a subset of these T cells remain behind as TRM. While TRM can be protective against microbial infection, it is becoming clear that autoimmune and autoinflammatory diseases in many tissues can be mediated by pathogenic TRM. will also discuss the important role these cells play in controlling infection as well as ongoing strategies to suppress and dislodge pathogenic TRM from involved tissues to reduce inflammation.

Dr. Jeffrey Rathmell will focus on how the metabolism of T cells can influence their specification into functionally distinct subsets in immunity and inflammation. Activation of T cells leads to a dramatic reprogramming of cell metabolism that is specific to each subset. The metabolic requirements of each T cell subset are distinct and may provide new approaches to selectively modulate immunity in normal settings as well as in inflammatory diseases or in treatment of cancer. Dr. Rathmell will discuss key nutrients and metabolic pathways that direct T cell subset specification and fate.

Dr. Ananda Goldrath will discuss the transcriptional control of TRM differentiation. CD8+ TRM are optimally positioned at common sites of pathogen exposure, where they elicit rapid and robust antiviral immune responses. However, the molecular signals controlling tissue residency and homeostasis of TRM remain unclear. Furthermore, tumor infiltrating lymphocytes (TIL) share a core TRM transcriptional signature which controls TIL residency. Dr. Goldrath will discuss the identification of novel transcriptional regulators in TRM differentiation and homeostasis by exploiting a dual-screening platform and integrating computational and RNAi in vivo screening approaches. hese findings provide novel insight into the biology of T cell residency, which could be leveraged to enhance vaccine efficacy or adoptive therapy treatments against cancer.

Dr. Todd Fehniger will focus on the biology of NK cells which are innate lymphoid cells that contribute to host antipathogen defense and can mediate anti-tumor responses. While classically considered innate immune cells, NK cells have been shown to “remember” prior activation events, including stimulation by cytokines and viral infection. These experienced NK cells differentiate into innate memory-like or adaptive NK cells. Dr. Fehniger will provide an overview of innate memory-like responses by NK cells, including a current understanding of mechanisms leading to persistent NK cell memory. Furthermore, he will discuss the biology of cytokine-induced memory-like NK cells, their role in enhanced anti-leukemia responses, and use of these cells in early-phase clinical trials as a form of cellular adoptive immunotherapy for leukemia patients.

Co-Chairs:

William R. Drobyski, MD
Medical College of Wisconsin
Milwaukee, WI

Warren D Shlomchik, MD
University of Pittsburgh
Pittsburgh, PA

Speakers:

Thomas S Kupper, MD
Brigham and Women's Hospital
Boston, MA
Tissue Resident Memory Cells

Jeffrey C Rathmell, PhD
Vanderbilt University Medical Center
Nashville, TN
T Cell Metabolism and Memory

Ananda Goldrath, PhD
University of California – San Diego
La Jolla, CA
Transcriptional Control of Memory T Cell Differentiation

Todd A Fehniger, MD,PhD
Washington University School of Medicine
Saint Louis, MO
Memory-Like Natural Killer Cells

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Joint Session: Scientific Committee on Iron & Heme and Scientific Committee on Transfusion Medicine

Swinging the Iron Pendulum: Loss and Gain Through Blood Donation and Transfusion

Iron is essential for many key biological processes, including hemoglobin production, but iron can also be toxic when present in excess. The body has developed elaborate mechanisms to regulate iron homeostasis. Gain or loss of iron, through blood transfusion or blood donation, disturbs systemic iron balance and can result in significant clinical consequences. This session will discuss recent insights into iron physiology as well as the clinical impact of blood transfusion and blood donation on iron homeostasis.

Dr. Laura Silvestri will discuss mechanisms that regulate systemic iron homeostasis, including those involving the hormone hepcidin and those that are hepcidin-independent. She will also discuss approaches for targeting hepcidin and its receptor, ferroportin, to correct iron disorders.

Dr. Caroline Philpott will discuss systems used by erythropoietic cells and other tissues to distribute iron within the interior of cells. She will focus on the intracellular iron-trafficking system, which delivers iron to sites of cofactor synthesis and prevents iron toxicity that is mediated by the reactivity of iron and oxygen.

Dr. Eldad Hod will discuss recycling of red blood cells and iron following transfusion therapy. In particular, he will focus on implications of the red blood cell storage lesion on iron homeostasis in the transfusion recipient.

Dr. Alan Mast will discuss the impact of blood donation on iron deficiency, and strategies to mitigate this deficiency. He will focus on differences in hemoglobin and iron store recovery following donation based on donor age, associated genetic variants, and donation frequency.

Co-Chairs:

Jeanne E. Hendrickson, MD
Yale University
New Haven, CT

Karin E. Finberg, MD, PhD
Yale School of Medicine
New Haven, CT

Speakers:

Laura Silvestri, PhD
San Raffaele Scientific Institute & Vita-Salute Uni.
Milan, Italy
Novel Insights Into Systemic Iron Regulation

Caroline Philpott
National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health
Bethesda, MD
Emerging Mechanisms of Cellular Iron Transport and Trafficking

Eldad A. Hod, MD
Columbia University Medical Center
New York, NY
Macrophage Recycling of Red Blood Cells and Iron Following Transfusion

Alan E. Mast, MD,PhD
BloodCenter of Wisconsin
Milwaukee, WI
Blood Donation and Iron Deficiency

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Scientific Committee on Blood Disorders in Childhood

A MAP(K) to Pediatric RASopathies

Multiple elements of the Ras pathway have been found to be mutated in human cancers and have therefore become a focus of intensive basic, translational and clinical research which will be highlighted in this session. In addition, clinical implications and future studies involving the Ras pathway will be discussed in each of the talks.

Dr. Li Qing will cover the basic biochemical and biophysical features of Ras proteins including Ras regulators and effectors in normal and diseased conditions. She will provide an overview of Ras-related mutations in Rasopathies and cancer and describe genetic mouse models of Ras. Dr. Qing will also review Ras isoforms and subcellular localization and will discuss current strategies to target Ras signaling.

Dr. Christian Kratz will review the current state of knowledge of syndromes caused by germline or mosaic aberrations in components of the Ras-MAPK pathway. He will focus on underlying molecular aspects as well as the cancer risk and cancer spectrum associated with these conditions, which are grouped in the following categories: Noonan syndrome and related disorders; neurofibromatosis type 1 and related disorders; mosaic RASopathies; RAS-MAPK pathway dysregulation without a Noonan-like phenotype; and RAS-MAPK pathway defects without overactivation.

Dr. Carl Allen will discuss the role of Ras pathway activation in pathogenesis of histiocytic disorders including Langerhans cell histiocytosis and rare variants including juvenile xanthogranuloma, Erdheim-Chester disease and Rosai-Dorfman disease.

Chair:

Anupama Narla, MD
Stanford University School of Medicine
Stanford, CA

Speakers:

Qing Li, MD, PhD
University of Michigan
Ann Arbor, MI
RAS-MPAK Pathway Signaling in Health and Disease

Christian P. Kratz, MD
Hannover Medical School
Hannover, Germany
Inherited Disorders of the Ras-MAPK Pathway

Carl E. Allen, MD,PhD
Texas Children's Hospital
Houston, TX
Acquired Hematologic Disorders of Ras-MAPK Activation

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Scientific Committee on Blood Disorders in Childhood Plasma Cell Neoplasia

Targeting Epigenetic Regulation in Myeloma

Perturbations of transcriptional regulation and chromatin structuring play a fundamental role in malignant transformation. Mutations and disruptions in epigenetic regulators are among the lesions commonly found in multiple myeloma (MM) and will be addressed in detail in this session.

Dr. Jonathan Licht will discuss epigenetic regulators in MM and how to provide therapeutic avenues in MM. He will specifically focus on one of the most common anomalies of epigenetic regulators in MM, which is the overexpression of NSD2/MMSET resulting from its fusion to the immunoglobulin locus in t (4;14). This chromatin modification is associated with active genes and prevents the action of the repressive resulting in aberrant gene expression, enhanced cell growth, altered responses to DNA damage, and resistance to chemotherapy.

Dr. Paola Neri will discuss enhancer deregulation in MM and promising therapeutic options for this disease. Immunoglobulin and non-immunoglobulin enhancers’ hijacking by variable genes is a recognized oncogenic driver event in MM. In addition, promiscuous rearrangements of the Myc locus is known to hijack enhancers and super-enhancers to dysregulate Myc expression in MM and are involved in its pathogenesis. Dr. Neri will discuss how the Bromodomain and Extra-Terminal Domain a master histone acetyl marker reader at enhancers loci regulating Myc, has led to promising therapeutic developments in MM and numerous other cancers.

Dr. Gareth Morgan will define the clinical application of epigenetic modifier mutations in MM. Epigenetic mutations/alterations found in next generation sequencing studies have been used to define prognostic relevance and outcome in patients with MM. Scanning the spectrum of mutations that are therapeutically tractable shows that rare cases may benefit from entry into basket studies investigating epigenetically active agents. Dr. Morgan will discuss how

Chair:

Irene M. Ghobrial, MD
Dana-Farber Cancer Institute
Boston, MA

Speakers:

Jonathan D. Licht, MD
University of Florida
Gainesville, FL
Epigenetic Regulation and Therapeutic Targeting in Myeloma

Paola Neri, MD
University of Calgary
Calgary, AB, Canada
Enhancer Deregulation in Myeloma

Gareth J. Morgan
University of Arkansas for Medical Sciences
Little Rock, AR
Clinical Application of Epigenetic Modifier Mutations in Myeloma

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Scientific Committee on Bone Marrow Failure

New Approaches to Correcting the Defect in Inherited Bone Marrow Failure Syndromes

The classic inherited bone marrow syndromes include Fanconi anemia, Dyskeratosis congenita (DC) and Diamond-Blackfan anemia (DBA). Over the last two decades, there have been significant advances in the understanding of the biological basis of these disorders. This session will focus on approaches to correcting these biological defects and discussing potentially new therapeutic strategies for this group of disorders.

Dr. Sergei Doulatov will discuss the role of autophagy in normal erythropoiesis and DBA. Given that induced pluripotent stem cells provide new opportunities for drug discovery, he will highlight unbiased chemical screens that depict a small molecule-inducer of autophagy, SMER28, enhancing erythropoiesis in a range of in vitro and in vivo models of DBA. These findings identify a novel therapeutic for DBA and implicate autophagy in early erythroid development.

Dr. Joel Greenberger will discuss the transforming growth factor-beta (TGF-B) signaling pathway and its role in Fanconi anemia. Fanconi anemia patients have a hyperactive TGF-B signaling pathway, which may explain reduction in hematopoietic stem cells and anemia. Dr. Greenberger’s lab developed double knockout (DKO) mice (SMAD3-/- Fancd2-/-) of four different combinations on the B6 and 129/Sv backgrounds. In all four breeding combinations, DKO mice were detected far below the 16 percent expected frequency. The surviving DKO mice resist TGF-B signaling, but still have the Fancd2-/- phenotype. These mice should be a valuable resource for understanding the role of TGF-B signaling in the absence of an intact Fanconi anemia pathway.

Dr. Christopher Lengner will address how enhancing a Wnt-Telomere feedback loop restores intestinal stem cell function in DC. He will also discuss how an isogenic DC cell model provides a platform for therapeutic discovery and identifies Wnt modulation as a potential strategy for treatment of DC patients. Patients with DC suffer from stem cell failure in highly proliferative tissues. Few therapeutic options exist for this disorder, and patients are treated primarily with bone marrow transplantation to restore hematopoietic function. Dr. Lengner’s lab generated isogenic DC patient and disease allele-corrected intestinal tissue using CRISPR/Cas9-mediated gene correction in induced pluripotent stem cells followed by directed differentiation into intestinal tissue. His research shows that DC tissue has suboptimal Wnt pathway activity causing intestinal stem cell failure and that treatment with the clinically relevant Wnt agonists LiCl or CHIR99021 restored TRF2 expression and reversed gastrointestinal DC phenotypes.

Chair:

Inderjeet Dokal, MD
Barts and The London School of Medicine and Dentistry
London, United Kingdom

Speakers:

Sergei Doulatov, PhD
University of Washington School of Medicine
Seattle, WA
Targeting Autophagy as a Therapeutic Pathway in Diamond-Blackfan Anemia

Joel S Greenberger, MD
UPMC Hillman Cancer Center
Pittsburgh, PA
TGF-B Inhibition Rescues Hematopoietic Defects in Fanconi Anemia

Christopher Lengner
University of Pennsylvania
Philadelphia, PA
Enhancing a Wnt-Telomere Feedback Loop Restores Intestinal Stem Cell Function in Dyskeratosis Congenita

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Scientific Committee on Hematopoiesis

Stress Hematopoiesis in Health and Disease

This session will describe the changes in hematopoietic stem cells (HSC) upon activation due to stress. It will address the metabolic changes that occur in HSC during stress; review how activation of HSC during regenerative stress alters activation and morphology of mitochondria; and highlight how granulocytes and endothelial cells in the bone marrow niche influence activation of HSC during regenerative hematopoiesis.

Dr. Toshio Suda will discuss purine metabolism and the impact of stress on hematopoietic progenitor stem cells. Quiescence and cell division of HSCs are regulated by the dynamic changes in metabolic status as well as in gene expression. Dr. Suda will highlight the role of the adenosine-Ca2+-mitochondria pathway on initiating HSC divisions as well as the role tumor suppressor genes (e.g., folliculin and TFE3) play in metabolic reprogramming and purinergic signaling of hematopoietic cells.

Dr. Marie-Dominique Filippi will demonstrate and discuss the concept of mitochondria driving the loss of HSC stemness after regenerative stress. During bone marrow regeneration, after transplantation, HSC exit quiescence to reconstitute the blood system, which is accompanied by activation of mitochondria and remodeling of their morphology. Mitochondrial morphology is permanently remodeled during and after division and as a result, HSC accumulate dysfunctional mitochondria after stress, thus disrupting the activity of the HSC progeny. Furthermore, irreversible remodeling of mitochondrial morphology also occurs during cumulative division under homeostasis. Using single cell RNAseq and functional assays, Dr. Filippi will show that mitochondria do not return to homeostatic conditions after HSC regeneration because HSC lack proper mitochondrial quality control, namely loss of mitochondrial dynamism.

Dr. Daniel Lucas will discuss recent discoveries in the bidirectional communication between neutrophils and endothelial cells. He will also highlight a critical regulator of emergency and regenerative hematopoiesis and how this regulation impacts the bone marrow niche.

Chair:

Stefan Karlsson, MD, PhD
Lund University
Lund, Sweden

Speakers:

Toshio Suda, MD,PhD
National University of Singapore
Singapore, Singapore
Purine Metabolism and Hematopoietic Stem and Progenitor Stem Cells Under Stress

Marie-Dominique Filippi, PhD
Cincinnati Children’s Hospital Medical Center
Cincinnati, OH
Mitochondrial Morphology Controls Hematopoietic Stem Cell (HSC) Self-Renewal and Confers HSC Divisional Memory

Daniel Lucas-Alcaraz, PhD
Cincinnati Children's Medical Center
Cincinnati, OH
Granulopoiesis in the Control of Hematopoietic Stem Cell Self-Renewal and Niches

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Scientific Committee on Hemostasis

Vascular Biology Components of Hemostasis

Hemostasis, the cessation of bleeding, is a complex process that includes the vessel wall and the cellular components in the intravascular compartment. This session will focus on two vessel wall components that have a major role in hemostasis and vascular wall function as well as new advances in understanding in common coagulation pathway.

Dr. Anna Randi will discuss the role of Von Willebrand Factor (VWF) in the regulation of angiogenesis and its dysregulation in angiodysplasia. The presentation will review in vitro and in vivo evidence demonstrating the role of VWF in angiogenesis and describe molecular pathways, including the angiopoietin/Tie-2 system and vascular endothelial growth factor signaling. In disordered angiogenesis, the abnormal process leads to severe, intractable gastrointestinal bleeding due to vascular malformations. This phenotype is found in all patients with congenital and acquired Von Willebrand Disease (VWD) as seen in aortic stenosis or in patients with left ventricular assist device implants.

Dr. Rodney Camire will present new advances in understanding of the common blood coagulation pathway. He will discuss novel mechanistic insights into the regulation of coagulation by factor V (FV) and tissue factor pathway inhibitor (TFPI). Dr. Camire will describe new biochemical and structural findings that reveal how these proteins interact to impact thrombin generation and the initiation of coagulation. Alternative splicing of FV to generate FV-short has a major influence on TFPI levels. This interaction has major impact on bleeding and modulating this interaction provides novel means to influence hemostasis.

Dr. Mukesh Jain will present the influence of Krüppel-like factors (KLFs) in thrombosis and hemostasis. He will discuss the role of KLFs as nodal regulators of both the blood and vascular systems. After an overview of how KLFs control development of various blood and vascular lineages, Dr. Jain will focus on how perturbation of KLF function contributes to the cellular and organismal response to acute (e.g., bacterial infection and sepsis/disseminated intravascular coagulation) and chronic disease states (e.g., metabolic disorders and atherothrombosis). He will further discuss correlative studies in human subjects to illustrate their therapeutic implications.

Chair:

Alvin H. Schmaier, MD
Case Western Reserve University
Cleveland, OH

Speakers:

Anna M Randi, MD, PhD
Imperial College London
London, United Kingdom
Von Willebrand Factor in Angiogenesis and Angiodysplasia

Rodney M. Camire, PhD
Perelman School of Medicine at the University of Pennsylvania
Philadelphia, PA
New Advances Along the Common Coagulation Pathway

Mukesh Jain
Case Western Reserve University / University Hospitals Health System
Cleveland, OH
Kruppel-Like Factors in Thrombosis and Hemostasis

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Scientific Committee on Lymphoid Neoplasia

Role and Mechanisms of Clonal Evolution in Lymphoid Malignancies

High-throughput sequencing techniques significantly accelerated the understanding of cancer genomes and uncovered a large amount of genetic variation between patients’ tumors as well as heterogeneity within tumors of the same patients. Most recent genomics studies have uncovered novel insights into disease dynamics of lymphoid neoplasms, providing evidence of clonal evolution over time driven by selective pressures during disease initiation, progression and therapeutic intervention. These studies have increasing implications for treatment resistance and dynamic biomarker testing as will be demonstrated in this session.

Dr. Charles Mullighan will discuss the genetic heterogeneity and evolution in acute lymphocytic leukemia in which clonal evolution patterns can be interpreted in the context of Darwinian evolution of founder clones and anti-leukemic therapy. Pivotal studies revealed that specific genomic alterations that facilitate resistance may be present in major or minor subclones at initial diagnosis or are acquired after commencement of therapy. Moreover, these alterations can confer resistance in drug-specific and drug-agnostic ways. The observation that the majority of relapsed-enriched alterations are present at diagnosis or early in therapy, often as subclones, indicates that sensitive mutation detection strategies are needed to anticipate and prevent relapse.

Dr. Dan Landau will address epigenetic heterogeneity in non-Hodgkin lymphoma, focusing on chronic lymphocytic leukemia (CLL) in which genetically distinct subpopulations are commonly observed and predict future evolutionary and clinical trajectories. Similar to the case of intra-tumoral genetic diversity, intra-tumoral epigenetic diversity occurs at the level of DNA methylation, leading to massive stochastic diversification in methylation patterns. Importantly, stochastic “epimutations” impact transcription, clonal evolution and clinical outcome. To robustly differentiate “epidrivers” from the majority of random passenger DNA methylation changes, a novel statistical inference framework has been developed that accounts for the varying epimutation rate across the genome. This framework can also include histone modifications revealing a decrease in the coherence between different epigenetic marks in CLL and consistent with intra-leukemic epigenetic diversity. Moreover, Dr. Landau will discuss multi-omic single-cell sequencing techniques that allow for tracking of epimutations and inferring high-resolution lineage trees.

Dr. Sarah-Jane Dawson will discuss clinical implications and biomarkers of clonal evolution using liquid biopsy approaches. Specifically, she will focus on recent technological advances in the detection and characterization of cell-free circulating tumor DNA that provide new opportunities for treatment tailoring based on real-time monitoring of tumor evolution. Liquid biopsies provide an alternative to tissue biopsies allowing noninvasive tumor genotyping and the serial analysis of genomic changes from a simple blood test. Dr. Dawson will highlight the uses of this technology to follow disease burden and track genomic changes in patients receiving novel therapies for lymphoid malignancies. She will also discuss promises and challenges in developing these tools for clinical application.

Chair:

Christian Steidl, MD
British Columbia Cancer Agency
Vancouver, BC, Canada

Speakers:

Charles G. Mullighan, MBBS, MD
St. Jude Children's Research Hospital
Memphis, TN
Genetic Heterogeneity and Evolution in Lymphoid Malignancies

Dan A. Landau, MD, PhD
Weill Cornell Medical College
New York, NY
Epigenetic Heterogeneity in Non-Hodgkin Lymphoma

Sarah-Jane Dawson
Peter MacCallum Cancer Center
Melbourne, Australia
Clinical Implications and Biomarkers of Clonal Evolution

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Scientific Committee on Megakaryocytes and Platelets

Thrombopoiesis Revised: From Lung to Hematopoietic Stem Cell Platelet Bias

Although platelets function primarily in hemostasis, they also participate in antimicrobial host defense, secrete cytokines that can induce inflammation, factors that aid tissue repair and development. To ensure a steady platelet supply, humans produce and remove ~1011 platelets daily, and the rate of production can rise sharply under conditions of platelet destruction. Hence, platelet production must be tightly regulated. Understanding the underlying biology of megakaryopoiesis is critical to the development of therapeutic modalities that can enhance platelet production in vivo or ex vivo. This session will present cutting-edge developments in the understanding of localization of megakaryocytes in the hematopoietic niche as well as their development from hematopoietic stem cells (HSCs).

Dr. Mark Looney will discuss the role of the lung circulation in platelet biogenesis using observations from intravital microscopy in mice. Classically, the bone marrow has been considered the primary site of platelet production. Recent imaging studies show that roughly half of platelets produced in the mouse circulation are from megakaryocyte-like cells that circulate through the lungs. During times of thrombocytopenic stress, megakaryocyte and other hematopoietic progenitors in the lung have the ability to migrate to the bone marrow and increase platelet production. Dr. Looney will highlight two populations of megakaryocytes in the lung along with the hematopoietic potential of lung-resident progenitor cells.

Dr. Katrin Heinze will discuss innovative technologies that allow improved spatial and temporal resolution by combining in vivo two-photon microscopy and in situ light-sheet fluorescence microscopy with computational simulations. Results from her studies reveal surprisingly slow megakaryocyte migration, limited intervascular space, and a vessel-biased megakaryocyte pool. These data challenge the current thrombopoiesis paradigm of megakaryocyte migration and support a modified model, where megakaryocytes at sinusoids are replenished by sinusoidal precursors rather than cells from a distant periostic niche. Furthermore, these data may have important clinical implications as therapies to increase megakaryocyte numbers might be sufficient to increase platelet counts in thrombocytopenic patients since megakaryocytes do not need to migrate to reach the blood vessel.

Dr. Claus Nerlov will discuss the evolving understanding of the diversity of HSCs and progenitors in the bone marrow with particular attention to those with megakaryocytic bias and potential. Recent studies using both mouse models and human stem cells have led to novel insights in the general hierarchical organization of hematopoiesis, as well as progenitor differentiation pathways. HSCs are more heterogeneous than previously thought; consisting of both platelet-biased and -restricted populations. In addition, stem cells are becoming increasingly platelet-restricted with age, indicating that age-related platelet bias could have clinical implications on the apparent decrease in the engraftment potential of aging stem cells in bone marrow transplantation.

Chair:

Jordan A. Shavit, MD,PhD
University of Michigan
Ann Arbor, MI

Speakers:

Mark Looney
University of California – San Francisco
San Francisco, CA
Platelet Biogenesis in the Lung Circulation

Katrin G Heinze
University of Würzburg
Würzburg, Germany
Spatial Regulation of Thrombopoiesis in the Bone Marrow

Claus Nerlov, PhD
Oxford University
Oxford, United Kingdom
Platelet-Biased Stem Cells and Their Role in Hematopoietic Aging

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Scientific Committee on Myeloid Biology

Regulation of Myelopoiesis by Inflammatory Signaling

Inflammation plays a critical role in regulating several aspects of normal and abnormal myeloid cell biology. This session will focus on the latest research in the field of microbiota and its regulation of neutrophil aging, complications of sickle cell disease (SCD), impact of chronic inflammation on hematopoietic stem cell (HSC) regulation and the role of chronic innate immune signaling in myelodysplastic syndromes.

Dr. Paul Frenette will discuss how the microbiota regulates neutrophil aging as well as the implications in the manifestations and complications of SCD. Aged neutrophils (i.e., those that have spent the most time in circulation) appear to drive vaso-occlusive episodes in SCD by increasing neutrophil adhesion and activation. Dr. Frenette will discuss molecular mechanisms as well as the new targets that offer novel opportunities for SCD therapies. 

Dr. Katherine King will discuss the role of chronic infection in stem cell regulation. HSCs are activated to divide during infections. Signaling through inflammatory cytokines and pathogen-associated molecular patterns are a common mechanism by which HSC activation occurs during infection. During chronic infection, persistent differentiation and restricted self-renewal results in depletion of the HSC compartment and, ultimately, pancytopenia. Dr. King will discuss the role further studies aiming to delineate molecular mechanisms of myeloid differentiation during infections may play in uncovering strategies to preserve HSCs during chronic inflammation.

Dr. Daniel Starczynowski will present findings and emerging concepts related to chronic immune response dysregulation in myelodysplastic syndromes (MDS). Chronic innate immune signaling in hematopoietic cells is widely reported in MDS. Innate immune pathway activation, predominantly via pattern recognition receptors, increases the risk of developing MDS. An inflammatory component to MDS has been reported for many years, but only recently has evidence supported a more direct role of chronic innate immune signaling and associated inflammatory pathways in the pathogenesis of MDS.

Chair:

Reuben Kapur, PhD
Indiana Univ. School of Med.
Indianapolis, IN

Speakers:

Paul S. Frenette, MD
Albert Einstein College of Medicine
Bronx, NY
Microbiota and Neutrophil Development

Katherine Y. King, MD, PhD
Baylor College of Medicine
Houston, TX
Stem Cell Regulation During Chronic Infection

Daniel T. Starczynowski, PhD
Cincinnati Children's Hospital Medical Center
Cincinnati, OH
Chronic Innate Immune Signaling in Myelodysplasia

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Scientific Committee on Red Cell Biology

Blood Building: How to Make a Red Cell

Erythroid cells are established following the sequential differentiation of hematopoietic stem cells (HSC). These steps are extrinsically modulated by their in vivo cellular environment and intrinsically controlled by transcriptional and post-transcriptional mechanisms that must operate properly in order to build a fully functional and responsive red cell. This session will describe the cellular and molecular events that establish this arc of differentiation.

Dr. Sean Morrison will describe the HSC niche, including mechanisms that promote HSC maintenance and erythropoiesis. He will also discuss the response to hematopoietic stresses that induce extramedullary hematopoiesis, particularly extramedullary erythropoiesis.

Dr. Esther Obeng will address how alternative splicing directly modulates the protein expression of genes involved in RNA processing, heme biosynthesis, and iron transport. Mutant the most commonly mutated splicing factor in acquired myelodysplastic syndromes (MDS), has been shown to cause aberrant 3’ splice site selection leading to altered isoform expression of transcription factors or introduction of premature termination codons in genes involved in iron transport. Dr. Obeng will discuss how these splicing changes have been implicated in the strong genotype-phenotype association between SF3B1 point mutations and subtypes of MDS with ring sideroblasts.

Dr. James Bieker will focus on how Erythroid Krüppel-like Factor (EKLF; KLF1) plays a critical role in coordinating the transcriptional onset and epigenetic changes that lead to erythroid-restricted gene expression. Although it was the first ß-like globin switching factor to be identified more than two decades ago, it is now also recognized to function as a global genetic regulator of erythropoietic differentiation. Recent studies in mice and humans have identified hypomorphic, truncated and altered function variants that implicate KLF1 in red blood cell disorders. Dr. Bieker will discuss these effects, along with more benign but clinically useful altered red cell properties that follow from haploinsufficient KLF1 expression levels, in the context of their potential therapeutic utility.

Chair:

Lily Huang, PhD
University of Texas Southwestern Medical Center
Dallas, TX

Speakers:

Sean Morrison
University of Texas Southwestern Medical Center
Dallas, TX
The Regulation of Hematopoietic Stem Cells and Erythropoiesis

Esther Obeng, MD, PhD
St. Jude Children's Research Hospital
Memphis, TN
Splicing Control in Normal and Aberrant Erythropoiesis

James J Bieker, PhD
Icahn School of Medicine at Mount Sinai
New York, NY
A Broad Spectrum of Red Blood Cell Disorders Due to KLF1 Variants

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Scientific Committee on Stem Cells and Regenerative Medicine

De Novo Generation of Blood and Progenitor Cells

Human pluripotent stem cells, which recapitulate normal development, serve as an emerging source of blood cells. This session will focus on the latest research involving the application of pluripotent stem cells including how these studies have enhanced the understanding of normal and malignant hematopoiesis and the generation of cellular immunotherapies.

Dr. Alexander Medvinsky will discuss development of the hematopoietic system in the human embryo compared to the mouse model. Specifically, he will focus on: the transient (yolk sac) and permanent (aorta-gonad-mesonephros [AGM]) regions of the hematopoietic system; the immunophenotype and the high regenerative potential of AGM-derived hematopoietic stem cells (HSCs); the molecular analysis of the human AGM niche, and the differences between mouse and human AGM hematopoiesis.

Dr. Dan Kaufman will discuss the use of human pluripotent stem cells to model early-stage human hematopoietic development and the challenge of deriving HSCs capable of long-term, multi-lineage engraftment. Additionally, he will discuss the use of human pluripotent stem cells as a novel source for cellular immunotherapies. Specifically, natural killer (NK) cells can be efficiently derived from both human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs), which can be engineered to better target refractory malignancies. hESCs and iPSCs also serve as a platform to express chimeric antigen receptors and other modifications to enhance anti-tumor activity. Importantly, hESC/iPSC-derived NK cells can be expanded to clinical scale in current GMP-compatible conditions. Since NK cells function as allogeneic cells, this strategy enables use of hESC/iPSC-derived NK cells as an “off-the-shelf” targeted cellular immunotherapy against refractory malignancies.

Dr. Eirini Papapetrou will present recent work on modeling myelodysplastic syndromes and acute myeloid leukemia using patient-derived and genome-edited human iPSCs. Specifically, she will present findings showing that hematopoietic stem/progenitor cells-derived iPSCs from patients with AML contain phenotypic and functional non-genetic heterogeneity that recapitulates a leukemia stem cell (LSC) hierarchy. In addition, Dr. Papapetrou will discuss how integrative omics studies and high-throughput small molecule and CRISPR screens can be leveraged to facilitate the identification of new therapeutic targets for LSCs.

Chair:

James Palis, MD
University of Rochester Medical Center
Rochester, NY

Speakers:

Alexander Medvinsky, PhD
University of Edinburgh
Edinburgh, United Kingdom
Development of Hematopoietic Stem Cells in the Human Embryo

Dan S Kaufman, MD,PhD
University of California – San Diego
La Jolla, CA
Human Pluripotent Stem Cell-Derived Blood Cells for Therapies

Eirini P. Papapetrou, MD, PhD
Icahn School of Medicine at Mount Sinai
New York, NY
Induced Pluripotent Stem Cells to Model Blood Diseases

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Scientific Committee on Thrombosis and Vascular Biology

Microparticles and Exosomes: Ready for the Clinic?

Extracellular vesicles (EVs) are cell-derived vesicles that circulate in blood at high concentrations and may be intimately involved in the pathogenesis of a broad array of vascular disorders. This session will provide an overview of the biology and measurement of EVs, with a focus on the ability of EVs to carry and transfer microRNA between cells and organs, how this property may be used to define new biomarkers and improve the understanding of vascular pathophysiology.

Dr. Francoise Dignat-George will discuss the diversity of EV origins and mechanisms of formation, as well as the impact of this diversity on EV composition and biological roles. She will also discuss the methods used to measure EVs in clinical samples, with a specific focus on standardization and relevance of EVs as emerging biomarkers in disease.

Dr. Jason Fish will present recent work focused on the contribution of circulating microRNAs to cardiovascular disease performed using animal models and human clinical samples. He will also describe the development of high throughput methodologies to measure the microRNA content of EVs and gene regulatory networks that are impacted by transferred microRNAs.

Dr. Louise Laurent will discuss the potential utility of microRNAs within EVs and other extracellular compartments as biomarkers for preeclampsia and other related conditions. She will also provide an overview of the promises and challenges in developing extracellular RNA isolation and analysis methods for clinical applications.

Chair:

Keith R. McCrae, MD
Cleveland Clinic
Cleveland, OH

Speakers:

Francoise Dignat-George
Aix-Marseille University - Faculty of Pharmacy
Marseille, France
Extracellular Vesicles: Overview and Clinical Implications

Jason Fish
University of Toronto
Toronto, ON, Canada
Endothelium-Derived Microparticles: Functions and Clinical Relevance

Louise Laurent, MD/PhD
University of California – San Diego
La Jolla, CA
Extracellular Vesicle microRNA: A Biomarker for Vascular Dysfunction in Pregnancy?

Other Scientific Sessions

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