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Scientific Program

Aberrant Transcriptional Regulation in Development and Malignancies - Live Q&A

Scientific Committee on Epigenetics and Genomics

This session will focus on mechanisms of altered gene expression driving malignant transformation. Chromosomal translocations that result in gene fusions are one of the earliest recognized oncogenic events leading to transformation. However, aberrant gene expression involving promoter to enhancer alterations, caused by chromosomal translocations and de novo mutations, have been reported. Understanding the mechanisms of altered gene expression, including the role of transcriptional regulators, may lead to the discovery of drugs that interfere with defective transcriptional control. 

Dr. Marc Mansour will specifically discuss mechanisms of oncogene activation in T-ALL, whereby somatic mutations in non-coding regions near an oncogene can create active regulatory elements?de novo.??Those newly formed enhancer elements create new binding sites for transcription factors such as MYB and ETS1, causing overexpression of the nearby oncogene. Identification of these gain-of-function mutations offer opportunities for improved patient characterization and potential treatment. 

Dr. Kathrin Bernt will give an overview of types of fusion in leukemia and describe in detail rearrangements that result in aberrant gene regulation as the key outcome. Using the recently described fusions of the Meningioma-1 gene as an example, Dr. Bernt will illustrate how enhancer hijacking by an intrinsically disordered nuclear protein results in aberrant epigenetic and transcriptional regulation that is sufficient to induce acute myeloid leukemia (AML). Mutations or rearrangements that affect the non-coding genome are often missed by standard diagnostic platforms, yet the epigenetic changes they induce may play critical roles in mediating malignant transformation. 

Dr. Jolanta Grembecka will discuss how insight into the mechanisms of transcriptional control may lead to the discovery of new promising drugs. The protein-protein interaction between menin and Mixed Lineage Leukemia 1 (MLL1) protein plays a critical role in defective gene regulation in acute leukemia with MLL1 translocations or with mutations in the nucleophosmin 1 (NPM1) gene. Dr. Grembecka will discuss the activity of small molecule inhibitors of the menin-MLL1 interaction in AML models, including patient-derived xenograft models derived from AML primary samples. The presentation will address single agent activity and combinatorial treatments with menin inhibitors and transcriptional changes induced by these compounds in AML models. 

Chair:

Ruud Delwel , MD, PhD
Erasmus MC Cancer Institute
Rotterdam,  Rotterdam, Netherlands

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AI, Data Science, Computer Vision and the Hematology Laboratory of the Future - Live Q&A

Scientific Committee on Hematopathology & Clinical Laboratory Hematology

Recent and profound advances in artificial intelligence (AI), data science, and computer vision are having a profound impact on many industries including medicine.  The clinical hematology laboratory and hematopathology are well-positioned to take advantage of this technological revolution to improve routine patient care and accelerate innovation.  This scientific session includes speakers who are at the forefront of developing and applying computational approaches for the quantitative analysis of tissue and liquid biopsy samples.  

Dr. Yinyin Yuan has spent the last decade developing machine learning methods to improve digital pathology.  She will discuss her group's discoveries in the geospatial organization of the tumor microenvironment and its implications for pathological analysis of tissue samples in the future.   

Dr. Metin Gurcan will discuss his experience in using digital images captured with whole-slide scanners to implement AI technology to large datasets.  He will also describe how such approaches will impact pathologic diagnoses. 

Dr. David Jaye will discuss the current state of the art in computer vision and AI use as well as the expectations and challenges faced by hematologists and hematopathologists in applying these new technologies for routine clinical care.  

Chair:

Scott J. Rodig , MD, PhD
Brigham & Women's Hospital
Boston,  MA

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Blood Therapeutics in Pandemics - Live Q&A

Scientific Committee on Transfusion Medicine

Emerging infectious diseases may affect blood safety and availability. However, even in the context of severe pandemics such as SARS-CoV-2, blood products continue to be essential therapies for patients with anemia, bleeding disorders, cancer, or post-trauma. Blood products may also prove to be effective in helping treat or prevent disease progression in infected patients. Using SARS-CoV-2 as a prototype, this session will address scientific approaches to ensure a safe and available blood supply during a pandemic and highlight recent cutting-edge research on the mechanisms by which passive immunotherapies (such as convalescent plasma) may reduce infections or their complications. The role of ABO glycoproteins in influencing infectious pathophysiology will also be discussed. Findings from this session will be applicable to other potential emerging infectious agents that could impact the health of patients with hematology and transfusion globally.? 

Dr. Ruchika Goel will present on our evolving understanding of the mechanisms by which passive immunotherapies [such as convalescent plasma and hyperimmune intravenous immunoglobulin (hIVIG)] may combat emerging infections, including the role of specific antibodies and antigenic targets.?She will summarize the current understanding of the effectiveness of convalescent plasma and hIVIG in the context of COVID-19. Dr. Goel will also elaborate on the influencers of the degree and persistence of neutralizing antibody response. 

Dr. Pampee Young will highlight challenges and solutions to securing a safe and available blood supply during pandemics, using the COVID-19 Pandemic Response as example.  COVID-19 has forced unusual changes not only on how and where we collect blood, but also demand of blood with precipitous drop early in the pandemic. Coupled with significantly increased demand in 2021, it was challenging for blood collectors to keep up.? She will review how a national blood collector met this dynamic situation and discuss lessons learned. 

Dr. Jacques Le Pendu will examine the role ABO glycoproteins play in infectious pathophysiology and related hematologic outcomes. He will first review the large body of literature on potential associations between COVID-19 and ABO blood groups. Dr. Le Pendu will then present an analysis of the available data based on potential underlying mechanisms to help clarify why blood group O may be associated with a lower risk of SARS-CoV-2 infection, shorter duration of stay in intensive care, or a lower risk of death. 

Chair:

Simone A. Glynn , MD,MPH
National Heart, Lung, and Blood Institute
Bethesda,  MD

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Cellular Memory and Innate Immune Pathways During Myeloid Cell Development and Infection - Live Q&A

Scientific Committee on Myeloid Biology

Innate myeloid hematopoietic cells have recently been recognized as retaining the memory of an initial immunological challenge to adapt their responses to secondary challenges. This concept was introduced by Dr. Mihai Netea in 2014, who named it ‘Trained Immunity’. Trained immunity has profound effects on how innate immune cells will respond to secondary challenges. Such response can be heightened or suppressed and confer beneficial effects to inflammation and response to infections. The mechanism behind trained immunity involves a complex interplay between metabolic adaptation and epigenetic modifications. Interestingly, the memory of prior immunological challenges extends well past the lifespan of innate immune cells. It is thus believed that trained immunity is carried by lifelong hematopoietic stem and progenitor cells (HSPCs). HSPCs respond equally to endogenous ligands that activate similar innate immune pathways to adapt their developmental response. This session will highlight recent cutting-edge research dissecting mechanisms of trained immunity as well as how these pathways can contribute to myeloid cell development.  

Dr. Mihai Netea will introduce the concept of trained immunity and discuss the metabolic changes that take place in the trained innate immune cells after infections and vaccinations, leading to an improved host defense.  

Dr. Sandrine Sarrazin will present new findings on how hematopoietic stem cells (HSCs) can directly sense cytokines and pathogen-associated molecular patterns such as toll-like receptor ligands conferring an innate immune memory. She will also discuss some therapeutic implications.  

Dr. Eirini Trompouki will review how transposable elements can induce innate immune signaling for hematopoietic stem cell development and regeneration, with impacts on HSC aging and trained immunity.   

Chair:

Marie-Dominique Filippi , PhD
Cincinnati Children's Hospital Research Foundation
Cincinnati,  OH

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From Structure to Function: Next Generation Iron Therapeutics - Live Q&A

Scientific Committee on Iron and Heme

Therapies for disorders of iron metabolism are rapidly progressing beyond venesection, chelation, and nutritional iron supplementation. Recent years have seen transformations in understanding the molecular and structural biology of systemic iron homeostasis and iron regulation. These findings have informed drug discovery, yielding a new era in iron therapeutics. Hepcidin is the master regulator of systemic iron homeostasis, and acts on the sole-iron export protein, ferroportin. The precise nature of this interaction has been unclear until recently.  

In this session, Dr Aashish Manglik will discuss his work defining the atomic-level structure of ferroportin and its interaction with hepcidin using cryogenic electron microscopy. Dr Manglik will describe the physiological implications stemming from this high-resolution view into how hepcidin binds to ferroportin, and how this may provide new foundations for the discovery of ferroportin modulators for therapeutic benefit. 

Heme synthesis occurs in the mitochondria, and heme synthesis enzymes would be expected to interact with “housekeeping” mitochondrial proteins structurally and functionally.? Dr Yvette Yien will discuss how model organisms have illuminated how ubiquitous mitochondrial proteins regulate heme synthesis in erythroid cells, and strategies for studying the function of critical housekeeping mitochondrial proteins.? She will specifically discuss how the ubiquitous CLPX mitochondrial protein unfoldase, regulates the heme synthesis pathway in erythroid cells and how these studies were inspired by earlier studies on yeast heme synthesis. 

Finally, Dr Dorine Swinkels will discuss next generation drugs for iron disorders, including iron deficiency, iron maldistribution and iron overload of various causes. Novel oral iron therapies for iron deficiency or maldistribution are emerging that combine ferric or ferrous iron with carriers or other compounds to optimize absorption and reduce adverse gastrointestinal effects. Optimal dosing regimens of oral iron supplements for iron deficiency have been defined using hepcidin profiles and iron stable isotopes. For iron maldistribution and iron overload disorders, among others novel therapies target hepcidin, erythropoiesis regulation of signal transduction pathways, and Hypoxia Inducible Factor Prolyl Hydroxylase.? Dr. Swinkels will review this work and focus particularly on unmet needs addressed, mechanism of action and strength of evidence of these novel drugs. 

Chair:

Sant-Rayn Pasricha , MD
Walter and Eliza Hall Institute of Medical Research
Fitzroy North,  VIC, Australia

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Immune Evasion and Immunotherapy in Myeloid Malignancies - Live Q&A

Scientific Committee on Myeloid Neoplasia

While immune checkpoint blockade, bispecific T cell engagers and adoptive cell therapy have been effective in  clinical trials for most hematologic malignancies, the full potential of immunotherapy in myeloid malignancies has not yet been discovered. Allogeneic hematopoietic stem cell transplantation (HSCT) provides compelling but indirect evidence that myeloid malignancies are immune responsive. However, T-cell specificities causing graft-versus-leukemia effect have been difficult to separate from those causing detrimental graft-versus-host reactivity. To highlight the potential of immunotherapy, this session will cover our current understanding of immune dysregulation and novel immunotherapy approaches in myeloid malignancies. 

Dr. Sergio Rutella will discuss mechanisms of immune evasion with a focus on acute myeloid leukemia (AML). The immune landscape of AML, including transcriptomic features of immune exhaustion and senescence, has been shown to correlate with chemotherapy resistance and response to T-cell targeting immunotherapies. Recent data have outlined the genomic correlates of immune infiltration in AML, providing evidence that TP53 mutational status is associated with an inherently immunosuppressed tumor microenvironment. Dr. Rutella will also review the cellular constituents and signaling pathways found to impact response to bispecific antibody immunotherapy, flotetuzumab.  

Dr. Johanna Olweus will illuminate how T-cells in allo-HSCT grafts can mediate cures in myeloid leukemia, and how anti-leukemic T-cell receptors (TCRs) can be selected from healthy donor T-cell repertoires. The TCRs targeting neoantigens or self-antigens can mediate efficient elimination of myeloid leukemia both in the acute, aggressive state, and minimal residual disease setting. These results bear promise that adoptive transfer of cells genetically modified to express therapeutic TCRs can be efficacious in the treatment of myeloid malignancies without graft-versus-host disease. 

Dr. Saar Gill?will discuss the interactions between myeloid malignancies and the surrounding residual normal hematopoiesis in the context of antigen-specific immunotherapies. Most antibody-based therapeutics (including chimeric antigen receptor-redirected T-cells) target lineage-associated antigens, implying that a certain amount of collateral damage to the normal counterparts of malignant cells is to be expected. While prolonged B-cell aplasia after CD19-specific immunotherapy is clinically tolerable, prolonged myeloid aplasia because of sustained attack by redirected T-cells is more challenging. Work from several groups has outlined a potential path forward, using gene editing tools to remove the shared antigen from normal cells, thereby effectively creating a leukemia-specific antigen de novo.? Dr. Gill will review this work and outline its implications for other immunotherapy targets and diseases. 

Chair:

Satu Mustjoki , MD,PhD
University of Helsinki
Helsinki,  Helsinki, Finland

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Immune Response to Old and New Enemies - Live Q&A

Scientific Committee on Immunology and Host Defense

A successful immune response to a viral pathogen is an intricately choreographed affair, involving coordination between the innate, adaptive, and memory immune response. SARS-CoV-2 has brought into sharp relief how heterogeneity in immune response, occurring at any point along the sequence of events, can lead to major differences in clinical outcome. Dysregulation of the immune response, including delayed, deficient, or overexuberant type I interferon response; dysregulated cytokine and chemokine release; and delayed antibody response have been implicated in poor outcomes. Other factors, including gender, age, and prior coronavirus exposure further contribute to heterogeneity in the immune response. This session will highlight recent findings identifying critical areas of coordinated anti-viral response and the mechanisms by which SARS-CoV-2 subverts them. Understanding the nature of the immune response that leads to recovery over severe disease is key to developing effective treatments for COVID-19. 

Dr. Akiko Iwasaki will discuss immune responses in COVID-19 patients with moderate and severe disease, highlighting how viral load, immune phenotype, and cytokines are predictive of mortality. She will also review signatures of cytokines and growth factors that associate with recovery vs. disease exacerbation and discuss autoimmune consequences of COVID-19 and their implications in long COVID. 

Dr. Alessandro Sette will discuss prediction of potential SARS-CoV-2 targets of T-cell immunity and immune responses in early convalescents. Immune correlates in the acute phase of disease suggest a key role for coordinated immunity and early T-cell responses, correlating with less severe disease outcomes. He will discuss the phenomenon of cross-reactivity between SARS-CoV-2 and common cold coronaviruses at the level of T-cell recognition and its potential role in modulation of disease severity and responsiveness to vaccination. Dr. Sette will characterize recent findings on the duration of immune responses following natural infection, the definition of the epitope repertoire for SARS-CoV-2 reactive T-cells, and the impact of variant-associated mutations on T-cell recognition. 

Dr. Marion?Pepper?will discuss characteristics of immune memory formed in response to mild COVID-19 or after mRNA vaccination.? She will focus on differences in SARS-CoV2-specific memory CD4+ T-cell and B-cell functions in vaccinated individuals with or without prior exposure to natural infection and the potential implications of these differences in viral control. 

Chair:

Katharine C. Hsu , MD, PhD
Memorial Sloan Kettering Cancer Center
New York,  NY

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JOINT Session - Gene Editing 2.0: Advances in Gene Editing to Treat Genetic Blood Disorders - Live Q&A

Scientific Committee on Blood Disorders in Childhood||Scientific Committee on Hematopoiesis

Programmable nucleases such as zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs), and CRISPR-Cas9 have had a major impact on life sciences and medicine by enabling efficient target gene disruption through double-strand DNA breaks. However, to benefit patients, most mutations that cause genetic diseases must be precisely corrected, rather than disrupted. This session highlights recent advances in gene editing technology that enhance precision gene editing efficiency in hematopoietic stem cells (HSCs) and avoid generating double stranded DNA breaks. The session will also cover how gene editing is evolving to treat blood disorders beyond beta-hemoglobinopathies, where it was first applied. 

Dr. Paula Rio will review the most recent updates in gene editing strategies, including new double strand break-free gene editing tools and their application in the correction of HSCs. Finally, Dr. Rio will detail her lab´s strategies to correct HSCs from Fanconi anemia patients, an inherited bone marrow failure syndrome in which homology directed repair is impaired. 

Dr. Punam Malik will discuss applications of novel gene editing approaches to treat beta-hemoglobinopathies.  Homology directed repair (HDR) remains a desirable means of gene editing, especially for diseases that manifest from an array of mutations in the same gene, relatively large deletions, or when specific sequences around the mutation do not allow efficient base editing.  However, HDR is relatively inefficient after a double strand break. In this presentation, Dr. Malik will review strategies that have been used to improve HDR including strategies from her lab. 

Dr. David Liu will discuss the development of two classes of base editors (Cytosine and Adenine base editors); proteins that enable point mutations to be installed or corrected at target positions in genomic DNA without making double-strand DNA breaks.  His lecture will present the integration of base editors with ex vivo and in vivo delivery strategies to address animal models of human genetic diseases including sickle cell disease and progeria with a high degree of phenotypic rescue and lifespan extension. 

Dr. Nicole Gaudelli will discuss the development and application of adenine base editors for hemoglobinopathies.  She will present strategies to treat hemoglobinopathies?by upregulating fetal hemoglobin as well directly editing the mutation responsible for sickle cell disease.  

Co-Chairs:

Alan B. Cantor , MD
Harvard Medical School
Boston,  MA

Simon Mendez-Ferrer , PhD
University of Cambridge
Cambridge,  Cambridge, United Kingdom

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Large Population Genomic Studies and Red Cell Disorders: A Revisionist View - Live Q&A

Scientific Committee on Red Cell Biology

In the past two decades, expanding knowledge of human genetics and its relation to disease onset and progression has contributed to transformational progress in the clinic. Genomic analyses of large populations studies have improved our understanding of the genetics of complex traits. By applying genome-wide association studies (GWAS) to blood cell traits, rare and low frequency variants have been identified that are clinically relevant. These large-scale studies are refining our view of blood disorders.  In this session, speakers will cover recent progress and advances in the understanding of human genetics related to red cells and other blood diseases. They will discuss approaches they employ to detect inherited genetic variations and evaluate how these impact blood disorders. Their topics include the identification of new genetic modifiers of sickle cell disease as well as the rise of clonal hematopoiesis and subsequent increased risk of malignancy. 

Dr.?Nicole Soranzo?will discuss the contribution of polygenic variation to blood traits and diseases. Genome wide association studies have revealed more than 10,000 inherited polymorphisms that contribute to traits derived from complete blood cell counts. The information from these genetic variants is combined into polygenic risk scores capturing a large proportion of heritability in blood trait phenotypes. She will discuss how the polygenic risk scores are then used to evaluate the contribution of inherited genetic variation to both malignant and non-malignant blood disorders. 

Dr. Laura Raffield will cover recent work to identify genetic modifiers for sickle cell trait and sickle cell disease associated complications (such as kidney disease and stroke), notably variants at the alpha globin locus. Dr. Raffield will lead a discussion of unpublished and ongoing work in cohorts from NHLBI’s Trans-Omics for Precision Medicine program (TOPMed). 

Dr. Steven McCarroll will examine clonal hematopoiesis (or clonally expanded blood cells with somatic mutations) commonly acquired with age and increase risk of blood cancer. Dr. McCarroll will review chromosomal alterations that are known to date to be associated with blood clones and discuss advances in identifying the underlying mechanisms.  His presentation will include the inherited genetic variations in genes associated with highly increased vulnerability to clonal hematopoiesis and the implications for malignancies. 

Chair:

Saghi Ghaffari , MD, PhD
Icahn School of Medicine at Mount Sinai
New York,  NY

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Lymphoid Neoplasia: Genetics of Predisposition and Precursors - Live Q&A

Scientific Committee on Lymphoid Neoplasia

Genetics play a major role in lymphomagenesis.  For inherited genetic factors, a number of large genome-wide association studies (GWAS) have identified variants associated with risk of lymphoma and lymphoma subtypes.  It is interesting to note the heterogeneity of inherited common variants across lymphoma subtypes and the contribution of rare inherited variants in lymphoma etiology.  Similarly, evidence on genetic contributions to lymphoma precursor conditions is growing.  Recent studies have reported the role of common inherited variants as well as acquired variants from next generation sequencing in lymphoma precursor conditions.  These studies are now providing insight into the genetic role across the continuum of normal to precursor condition to lymphoma development.   

Dr. James Cerhan will discuss the role of inherited variants that have the potential to cause lymphoma.  He will provide an overview of genomic studies including the impact of rare and common variants. He will then dive into the commonalities and heterogeneity across lymphoma subtypes and end with the current status of translating these inherited variants to the clinic. 

Dr. Geffen Kleinstern will discuss the role of inherited variants with risk of monoclonal B-cell lymphocytosis (MBL), the precursor to chronic lymphocytic leukemia (CLL). She will also present results on the role of acquired variants with progression from MBL to CLL.  She will provide details of two genomic scores comprised of the inherited or somatic variants, respectively, and their impact on etiology of MBL and on outcome among individuals with MBL.  

Dr. Sandrine Roulland will discuss the role of early lesions in the development of follicular lymphoma (FL).  She will discuss the genetic landscape of FL common precursor cells (CPC) as well as the role of transcriptome and epigenomic changes.  She will also discuss the role of the microenvironment on CPC and possible opportunities for novel therapy.  

Chair:

Susan L. Slager , PhD
Mayo Clinic
Rochester,  MN

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Molecular Basis of Disease Progression in Plasma Cell Precursor Diseases - Live Q&A

Scientific Committee on Plasma Cell Neoplasia

Multiple myeloma and related plasma cell disorders are typically preceded by an asymptomatic precursor phase, monoclonal gammopathy of undetermined significance (MGUS), and in some individuals an intervening phase termed smoldering multiple myeloma (SMM). Epidemiological studies suggest that the precursor stages can be present for over a decade prior to clinical diagnosis of myeloma. Most patients with MGUS will never require therapy, and studies of large cohorts of affected individuals have allowed development of clinical risk stratification tools that can identify those at highest risk of progression. Unlike most cancers, the long precursor phase provides an opportunity for early intervention, potentially altering the natural history of the disease, thus leading to significant interest in identifying the biology behind disease progression. Studies over the last decade have started uncovering the genetic complexity of clonal plasma cells and the impact of the tumor microenvironment on this process.  This session will highlight the progress made in recent years that will enable us to develop effective prevention and treatment strategies with a real potential for cure in some patients.  

Dr. Giada Bianchi will discuss the role the bone marrow niche plays in the progression of precursor plasma cell disorders, MGUS, and SMM to active multiple myeloma. Beyond clonal evolution in clonal plasma cells, a growing body of data support a pivotal, pathogenetic role for both the soluble and cellular bone marrow microenvironment in the malignant evolution of plasma cell disorders. Dr. Bianchi will review this data with a special emphasis on novel information obtained through omic approaches. 

Dr Niccolo Bolli will review novel acquisition in genomics of myeloma and its related asymptomatic precursor diseases. Recent studies have highlighted differences in the catalogue of genomic abnormalities of MGUS and SMM that may help understand their basis of progression. More than mutations, focus will be placed on structural abnormalities and mutational signatures, i.e., features that are not easily captured by targeted next-generation sequencing panels but seem to be closely associated with progression. These findings may provide a prognostic stratification and ultimately a more accurate classification aligned with the biology of the disease.? 

Dr.?Sigurdur Kristinsson will discuss the role of early detection and intervention in multiple myeloma. His talk will focus on progression in MGUS and SMM. Dr. Kristinsson will provide insight into molecular mechanisms and potential targets for early intervention in multiple myeloma precursor disease. 

Chair:

Shaji Kumar , MD
Mayo Clinic
Rochester,  MN

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Novel Findings in CAR-T Cell Therapies for Hematologic Malignancies - Live Q&A

Scientific Committee on Transplantation Biology and Cellular Therapies

T-cells genetically modified with chimeric antigen receptors (CAR-T) have had unprecedented efficacy in patients with lymphoid malignancies, including several B-cell malignancies and multiple myeloma. Since 2017, there have been five CAR-T cell products approved by regulatory authorities for use in the relapsed or refractory setting; four of these, target the CD19 antigen present in most B-cell malignancies, and one targets the B cell maturation antigen (BCMA) in multiple myeloma. The different CAR-T products are roughly comprised of an antigen-binding domain, a hinge or spacer domain, a transmembrane domain, and intracellular signaling domains that include portions of receptors that mediate T-cell activation and co-stimulation. There has been tremendous growth in the clinical development of novel CAR-T cell therapeutic products, the scientific understanding of how CAR-T cells exert their efficacy and toxicity, the mechanisms of early and late disease resistance and relapse. This session will highlight recent cutting-edge research in CAR-T cell design and downstream effects as well as real-world mechanisms of resistance and approaches to next-generation CAR-T cell therapeutics.  

Dr. Marcela Maus will discuss the mechanisms underlying CAR-T cell function as driven by differences in co-stimulation, antigen binding, signaling, transcriptional profiling, and T-cell effector functions. Recent data have emerged that indicate each portion of the molecular construct of a CAR-T cell has a role in determining its fate. Additionally, different tumors and their microenvironments also appear to influence CAR-T cell function. 

Dr. David Baker will focus on synthetic biology, including synthetic genes, novel “from-scratch” protein design, and advances in deep learning-based structure modeling. He will discuss advanced technologies used to compute and predict protein folding which can then be tested experimentally. Dr. Baker will also describe combinatorial logic systems that can be applied to CAR-T cell targeting and design and using these technologies with de novo SARS-CoV2 candidate therapeutics.   

Dr.?Marco Ruella will discuss recent findings on mechanisms leading to failure of CAR-T cell immunotherapy in B-cell leukemia and lymphoma patients. In particular,?he will discuss the role of apoptosis resistance in leukemic cells, the risk of accidental CAR transduction of leukemic blasts, and the role of antigen escape. Dr. Ruella will present novel therapeutic approaches to overcome resistance that take advantage of novel CAR designs and combinations with small molecules. 

Chair:

Marcela V. Maus , MD
Massachusetts General Hospital, Harvard Medical School
Lexington,  MA

Speakers:

Marcela V. Maus , MD
Massachusetts General Hospital
Boston,  MA
Signaling in CAR-T cells

David Baker , PhD
University of Washington
Seattle,  WA
Combinatorial Signaling in CAR T Cells

Marco Ruella , MD
University of Pennsylvania
Philadelphia,  PA
Resistance Mechanisms to CAR-T Cells in ALL

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Platelets, Megakaryocytes and the Immune Continuum - Live Q&A

Scientific Committee on Megakaryocytes and Platelets

Megakaryocytes give rise to platelets, which have important roles in hemostasis, coagulation, mounting of an appropriate immune response, inflammation, and tissue repair. As a first line of defense, platelets express numerous receptors that bind pathogens, which allows platelets to efficiently destroy the invaders, or present them to cells of the immune system. Activated platelets secrete and express many pro-inflammatory molecules that attract, and capture circulating leukocytes and direct them to inflamed tissues. Both platelets and megakaryocytes can also uptake, process, and present antigens to CD8+ T-cells, demonstrating that these entities can directly alter an adaptive immune response. Modulation of platelet production often resulting in thrombocytopenia is a critical sentinel during mild and severe infection. In this session three experts will discuss their work assessing platelets and megakaryocytes as key components of the innate immune system and important players in the immune continuum.  

Dr. Milka Koupenova will discuss the immune role of platelets with respiratory viruses, focusing on the role of SARS-CoV-2 in platelet "death". The presentation will include in vivo data obtained from platelets isolated from COVID-19 patients, and results from in vitro treatment of platelets with purified SARS-CoV-2 (wild-type strain). 

Dr. Robert Campbell will discuss the role of megakaryocytes and platelets in viral infections.? While megakaryocytes and platelets are thought to primarily participate in hemostasis and thrombosis, recent data from multiple laboratories suggests they are significant players in viral infections. This work indicates viral infections alter the transcriptome and proteome of megakaryocytes and platelets, which in turn changes their function. Dr. Campbell will review this work and focus on how altered gene expression allows megakaryocytes and platelets to help fight viral infection while also increasing platelet reactivity and thrombotic risk. This will include data from megakaryocytes and platelets in the COVID-19 setting. 

Dr. Craig Morrell?will discuss lung megakaryocyte immune characteristics and functions. Recent data from multiple groups demonstrates that lung megakaryocytes are more immune differentiated than those in bone marrow.? Dr. Morrell will review these data and discuss how the tissue environment shapes megakaryocyte immune characteristics.? In addition, the potential sources for lung megakaryocytes will be introduced as well as changes in lung megakaryocytes in disease models in vivo.? 

Chair:

Elizabeth E. Gardiner , PhD
Australian National University
Canberra,  ACT, Australia

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Regulators of Hematopoietic Stem Cell Development and Expansion: Bench to Bedside - Live Q&A

Scientific Committee on Stem Cells and Regenerative Medicine

A low stem cell dose and lack of human leukocyte antigen-matched donors are major barriers to hematopoietic stem cell (HSC) transplantation and gene therapies. Ex vivo expansion of somatic HSCs or de novo HSC production from pluripotent stem cells can overcome these limitations and broaden HSC application for treating hematologic and immune system diseases. This session will highlight recent advances in the understanding of regulators of HSC development and self-renewal along with therapeutic application of expanded HSCs.  

Dr. Hanna Mikkola will discuss mechanisms that regulate the generation of self-renewing HSCs during human development and elucidate how single-cell and spatial transcriptomic approaches have illuminated this process.? Although it is widely accepted that HSCs originate from hemogenic endothelium, the precise characteristics of the unique endothelial cells that generate HSCs rather than embryonic progenitors have been poorly defined.? She will discuss new methods of identifying nascent HSCs in the human aorta-gonad-mesonephros region and extraembryonic tissues. In addition, Dr. Mikkola will describe how these methods can be used to follow HSC colonization and expansion in the fetal liver as they acquire phenotypic and functional properties of mature HSCs. Finally, she will outline the important role the molecular map of human HSC development has in helping guide the differentiation of human pluripotent stem cells to fully functional, transplantable HSCs in culture. 

Dr. Sauvageau will discuss the issue of hematopoietic stem cell expansion with a focus on the small molecule and gene regulators of self-renewal, which have potential applications in the clinical arena. He will also discuss the benefits of stem cell rejuvenation through partial epigenetic reprogramming and discuss the merit of expansion/reprogramming for the next generation of stem cell transplants. 

Dr. Yamazaki will highlight recent technological advances in expansion of mouse and human HSCs. Using PVA-based media in combination with optimized concentration of stem cell factor, thrombopoietin, and insulin, his research was able to achieve up to an 899-fold expansion of purified mouse HSCs over the course of a month. His research has also demonstrated that a similar approach can be used to expand human HSCs, although less efficiently than mouse HSCs. Dr. Yamazaki will also discuss media and stem culture optimization steps that can be used to enhance ex vivo expansion of human HSCs. 

Chair:

Igor I Slukvin , MD
University of Wisconsin Madison
Madison,  WI

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Ribosomes in Hematopoiesis and Disease - Live Q&A

Scientific Committee on Bone Marrow Failure

Ribosomes are key components of cellular metabolism, and it is remarkable that acquired and germline defects in ribosomes can be both tolerated and associated with a significant range of phenotypes, with hematopoietic abnormalities most prominent.  

Dr. Kim De Keersmaecker will discuss recent insights into the molecular mechanisms by which ribosomal protein defects in ribosomal protein genes can cause bone marrow failure and cancer development.   

Dr. Michaela Fontenay will describe the characteristics of ribosome biogenesis during the course of normal murine and human erythropoiesis. She will also discuss the regulatory mechanisms that control the production of ribosomal subunits and the decline in their production in mature erythroblasts. Dr. Fontenay will review the mechanisms and consequences of ribosome dysfunction on ineffective erythropoiesis in myelodysplastic syndromes. Lastly, Dr. Fontenay will examine the impact of low ribosome availability on RNA decay and protein translation.  

Dr. Patrick Revy will describe a new mechanism by which hematopoietic cells in persons with Shwachman-Diamond syndrome (SDS) might be rescued. In Mendelian diseases, somatic genetic rescue (SGR) corresponds to the spontaneous occurrence of somatic genetic events that offset the pathogenic effect of germline mutations at the cellular level, leading to genetic mosaicism and, in some cases, a milder disease phenotype. SDS is a leukemia predisposition disorder caused by germline biallelic mutations in the SBDS or EFL1 genes.??SBDS and EFL1 deficiencies are considered as ribosomopathies since they lead to impaired ribosomal subunit joining and reduced protein synthesis because of defective eIF6 eviction from the 60S subunit. Dr. Revy will present recent data demonstrating that acquisition of somatic EIF6 mutations is a frequent mechanism of?somatic genetic rescue in hematopoietic cells in SDS.? Dr. Revy will examine how SGR in SDS may have important diagnostic, therapeutic, and clinical consequences. 

Chair:

Stella m Davies , PhD, MBBS, MRCP
Cincinnati Children's Hospital
Cincinnati,  OH

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Unraveling the Genetics of Bleeding: From Genotype to Phenotype - Live Q&A

Scientific Committee on Hemostasis

Inherited bleeding disorders are caused by DNA variation that adversely impacts the function of genes important for hemostasis.  Recent advances in DNA sequencing have enabled remarkable scientific advancements in hemostasis. However, there are remaining challenges to realizing the full potential of the human genome. This session will discuss state-of-the-art research furthering our understanding of inherited bleeding disorders and bleeding disorder complications. 

Dr. Keith Gomez will describe genomic testing techniques developed during the human genome project and their impact on the field of hemostasis. These high-throughput sequencing techniques have been used to revolutionize our understanding of the molecular basis of heritable bleeding disorders. These techniques are being integrated into pathways for routine patient care. While this will enhance the process for identifying causes of hemostatic diseases, it also presents challenges in pathogenicity classification, and dealing with incidental findings and variants of uncertain significance. Dr. Gomez will discuss the strengths and limitations of genomic testing technology, how this can improve the management of haemostatic disease and strategies for meeting these challenges. 

Dr. Samantha Gouw will discuss the genetic basis of hemophilia A. A great variety of causative mutations in the F8 gene have been described. She will focus on genotype-phenotype relations in mild, moderate, and severe hemophilia A. Dr. Gouw will also review current data on genetic determinants of the development of inhibitory anti-factor VIII antibodies. Null mutations carry a higher risk of inhibitor development than non-null mutations. Dr. Gouw will discuss data on the relation between genetic variation in immune modulatory genes and inhibitor development.  

Dr. Doug Fowler will focus on the large and growing problem of newly discovered DNA variants that often cannot be definitively interpreted. Many?are instead?deemed?variants of uncertain significance (VUS). VUS are a large?and growing roadblock in the use of genetic information. Dr. Fowler will describe the deep mutational scanning (DMS) technology used to experimentally test the consequences of thousands of missense variants simultaneously.  The result of DMS is a comprehensive variant effect map containing functional data for nearly all possible missense variants of a gene. By revealing the mechanisms of variant effects, such maps can empower variant interpretation. Dr. Fowler will discuss DMS of two genes implicated in inherited bleeding, Vitamin K Epoxide Reductase (VKOR) and Factor IX (F9).   

Chair:

Jill M. Johnsen , MD
Bloodworks and University of Washington
Seattle,  WA

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Viral and bacterial infections - basic insights into vascular biology and coagulation - Live Q&A

Scientific Committee on Thrombosis and Vascular Biology

Infections are often associated with coagulation disorders. All aspects of the coagulation cascade (i.e. primary hemostasis, coagulation, and fibrinolysis) can be affected. Consequently, thrombosis and disseminated intravascular coagulation, hemorrhage, or both, can occur. There is longstanding interest in the interplay between infections, inflammation, immunology, and coagulation, which has increased tremendously during the SARS-CoV-2 pandemic. This session will present cutting-edge research on pathways by which viruses and bacteria influence the vascular endothelium, coagulation, and the immune system.   

Dr. Eric van Gorp will discuss the mechanisms of thrombosis and bleeding in viral infection. Dr. van Gorp will discuss what we know?about?pathogenesis and how it impacts clinical practice.?Viruses can divide and result in bleeding [hemorrhagic?viral infections such as Ebola, hanta, dengue] and thrombosis?[e.g. influenza, corona]. Dr. van Gorp will discuss results from both clinical studies as well as animal and cell/tissue models.? The SARS-CoV-2 pandemic has shed light on research?into the relationship between viruses and the hemostatic?mechanism, as such, Dr. van Gorp will also discuss how we can use these data to gain broader?insight into the relationship between viruses and coagulation. 

Dr Jason Knight will delve into the concept of immunothrombosis. The COVID-19 pandemic has provided a rare opportunity to intensively study the interplay between immunology and coagulation in infectious disease. Dr. Knight will discuss how the innate and adaptive arms of the immune system contribute to the hypercoagulability seen in many patients with severe COVID-19. He will also discuss potential implications for non-COVID infections. 

Dr. Katherine Hajjar will present what is known about endothelial activation in infectious diseases. She will review key, clinically relevant aspects of endothelial cell dysfunction associated with severe infectious disease.? Dr. Hajjar will also discuss induction of a proinflammatory phenotype, perturbation of endothelial cell thromboresistance properties, development of pro-adhesive events, and alterations in vascular tone, all of which can contribute to vascular thrombo-occlusion.?Wherever applicable, she will address implications for therapy. 

Chair:

Saskia Middeldorp , MD,PhD
Radboud University
Nijmegen,  Nijmegen, Netherlands