Scientific Program

Program Chair:

Kojo Elenitoba-Johnson, MD,
New York, NY

Co-Operativity in the Pathogenesis of Myeloid Malignancies

Saturday, December 9, 2023, 2:00 p.m. - 3:15 p.m. Marriott Marquis San Diego Marina, Marriott Grand Ballroom 11-13

This session was developed by the Scientific Committee on Myeloid Neoplasia.

Myeloid malignancies are characterized by recurrent somatic mutations and cytogenetic aberrations. Individual mutations and co-mutation patterns correlate with response to treatment and prognosis. This scientific session will explore the interaction patterns of disease-associated genetic and epigenetic factors by describing the landscape and order of acquisition of such correlations, including mutation analysis at the single cell level, interplay between gross chromosomal aberrations and gene mutations, and their implications for our understanding of disease pathogenesis, treatment response, and prognosis.  

Dr. Seishi Ogawa will discuss the interplay between chromosomal alterations and gene mutations in the pathogenesis of myeloid neoplasms. He will give an overview of genetic studies that have revealed significant correlations between lesions in major subtypes of myeloid neoplasms and clonal hematopoiesis. The interplay is shown to shape clonal evolution during leukemogenesis. Dr. Ogawa will also discuss the functional basis of some of these correlations and their impact on therapeutics.  

Dr. Linde Miles will describe clonal evolution at the single cell level and outline its potential clinical implications. She will provide an overview of single cell DNA sequencing and multi-modal technologies used to examine clonal heterogeneity and genotype-immunophenotype relationships in acute myeloid leukemia (AML) patient samples. Dr. Miles will discuss findings that suggest that single cell multi-omics analysis of clonal architecture, mutation order, and immunophenotype of patient samples can help to predict response of patients on treatment regimens used in AML patients.  

Dr. Mark Dawson will discuss the role of non-genetic mechanisms that influence cancer cell fitness. Currently, personalized cancer medicine is focused on understanding the genetic mutations in an individual’s cancer and designing targeted therapies. This dogma rests on the premise that differences in cancer cell behavior can only be explained by different genetic mutations. However, emerging work from the Dawson lab and others have challenged this dogma and demonstrated that genetically identical cancer cells can behave very differently in various tissue environments and in response to therapeutic pressure. Dr. Dawson will discuss work from his lab which has shown that non-genetic or “epigenetic” factors are as important as genetic factors in the behavior of myeloid cancers. 

Chair:

Saar Gill, MD, PhD
University of Pennsylvania School of Medicine
Philadelphia,  PA

Speakers:

Seishi Ogawa
Kyoto University Graduate School of Medicine
Sakyoku,  KYO, Japan
Interplay Between Chromosomal Alterations and Gene Mutations

Linde A. Miles, PhD
Cincinnati Children's Hospital Medical Center
Cincinnati,  OH
Single Cell Mutation Analysis of Clonal Evolution and Its Clinical Implications

Mark A. Dawson, MBBS,PhD,FRACP,FRCPA
Peter Maccallum Cancer Centre
Melbourne,  VIC, Australia
Beyond Somatic Mutations in the Pathogenesis of Myeloid Neoplasia

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Emerging Methodologies to Investigate Platelet Biology

Saturday, December 9, 2023, 2:00 p.m. - 3:15 p.m. San Diego Convention Center, Room 25

This session was developed by the Scientific Committee on Megakaryocytes and Platelets.

Blood platelets are increasingly recognized as playing versatile roles in hemostasis and thrombosis, innate immunity, and tumor growth regulation. This scientific session will highlight state-of-the-art methodologies that have emerged in recent years to investigate the cell biology of platelets and megakaryocytes, their precursors. The first two presentations will focus on innovative imaging technologies to observe bone marrow megakaryocytes and blood platelets through electron tomography and dynamic live imaging, respectively. The third presentation will focus on novel next generation sequencing methodologies used to determine genetic and genomic factors contributing to individual platelet parameter variability. 

Dr. Anita Eckly will present 3D imaging of megakaryocytes with electron tomography and large volume Focused Ion Beam-Scanning Electron Microscopy (FIB-SEM), Focused ion beam (FIB) SEM providing insight into the substructure of MKs in their native environment at ultrastructural resolution. She will list their advantages and limitations, the resolution that can be achieved, the technical difficulties, and applications in megakaryocyte biology. For example, she will highlight how these approaches can help to further the understanding of megakaryocyte crossing through bone marrow sinusoids and their functional interactions with neutrophils. To conclude, Dr. Eckly will discuss some future perspectives with respect to recent cryo-EM techniques developments and correlative live-imaging. 

Dr. Florian Gaertner will discuss live-cell imaging techniques that allow tracking and morphological analysis of individual platelets in thrombosis and inflammation.  The breakdown of vascular barriers in inflammatory diseases is a major complication, and platelets play a crucial role in safeguarding inflamed blood vessels. Dr Gaertner will discuss live cell imaging techniques that allow tracking and morphological analysis of individual platelets in thrombosis and inflammation in vitro and in vivo. Using these techniques, his group has shown that platelets form lamellipodia in vivo to spread on the inflamed vasculature, enabling haptotactic migration along adhesive gradients. Disruption of haptotaxis impairs platelet repositioning, compromising vessel sealing and causing microbleeds. Platelets also migrate to capture bacteria during infection, preventing them from spreading throughout the body. 

 

Dr. Andrew Johnson will review how advances in sequencing technologies scaled to populations and clinical samples are changing our understanding of platelet biology including the discovery of new gene loci and the ability to provide diagnoses for rare platelet, thrombotic and bleeding disorders (BTPD). This includes application of gene-mapping and sequencing strategies to find determinants of variation in platelet count and platelet function. It also extends to the development of targeted sequencing panels with high levels of evidence and application of exome and genome sequencing in affected individuals and families. Furthermore, the role of platelet transcriptome (RNA) sequencing will be described for understanding platelet function, genetic cases and in prediction of disease outcomes (e.g., tumor-educated platelets). Finally, the results of a global survey of BTPD practitioners will be summarized identifying prevalent approaches to application of sequencing and functional testing, along with potential gaps in practice. The audience members will learn more about the application of Genetics to BTPD in current practice (for example ISTH Gold Variants, ClinGen), complemented with specific functional testing, as well as emerging areas of other OMICs (for example platelet RNA-seq and proteomes) for diagnosis and characterization of clinical cases. 

Chair:

Herve Falet, PhD
Versiti Blood Research Institute
Milwaukee,  WI

Speakers:

Anita Eckly, PhD
UMR_S1255 Inserm-Université de Strasbourg
Strasbourg,  France
High-Resolution 3D Imaging of Megakaryocytes

Florian Gaertner, MD, PhD
LMU Klinikum
Munich,  Germany
Dynamic Live Imaging of Platelets

Andrew D. Johnson, PhD
National Heart, Lung, and Blood Institute, The Framingham Heart Study
Framingham,  MA
Next Generation Sequencing in Platelet Biology

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Interplay of Coagulation and Complement in Transfusion Medicine

Monday, December 11, 2023, 2:45 p.m. - 4:00 p.m. San Diego Convention Center, Room 29

This session was developed by the Scientific Committee on Transfusion Medicine.

While transfusion is one of the most routine therapeutic interventions in hospitalized patients, transfusion is not without risk. Exposure to blood products and similar biologics, such as heparin, can lead to serious complications that can cause significant morbidity and mortality. Among complications, delayed hemolytic transfusion reactions (DHTRs) accompanied by hyperhemolysis, which often mimic underlying disease exacerbations in patients with sickle cell disease (SCD), transfusion associated acute lung injury (TRALI) and heparin-induced thrombocytopenia (HIT) can be some of the most severe. While a limited understanding of the pathophysiology of these reactions has prevented a more targeted approach to treating and even preventing these reactions, this session will highlight recent developments in this field that have uncovered key features of the underlying immunological mechanisms responsible for DHTRs, TRALI, and HIT with implications in more effective treatment and prevention strategies.  

Dr. Satheesh Chonat will discuss the role of complement in the development of DHTRs with hyperhemolysis and the underlying pathophysiology of SCD in general. By leveraging a series of translational studies and preclinical models, he will discuss the underlying the susceptibility of Sickle RBCs and endothelium to complement-mediated injury during transfusion-associated hemolysis and other SCD complications, while also exploring the potential role of complement inhibitory approaches in the treatment of acute SCD complications.  

Dr. Rick Kapur will define key features of the underlying pathophysiology of TRALI, with a particular focus on the role of complement in this transfusion reaction.  Data generated from clinical and preclinical studies will be presented that focus on the role of complement in facilitating macrophage activation and neutrophil-extracellular trap formation that ultimately contributes to the development of TRALI.

Dr. Demin Wang will focus on the pathophysiology of HIT. He will provide an overview of the immune pathogenesis of HIT and the origin of B cells that produce protein platelet factor 4 (PF4) in a complex with heparin (H)-specific antibodies. He will also explore how the breakdown of B cell peripheral tolerance contributes to the production of pathogenic PF4/H-specific antibodies. He will then highlight the molecular and functional properties of pathogenic PF4/H-specific antibodies and offer new approaches to the diagnosis and treatment of this condition.  

Chair:

Sean Stowell, MD
Brigham and Women's Hospital/Harvard Medical School
Boston,  MA

Speakers:

Satheesh Chonat, MD
Children's Heathcare of Atlanta
Atlanta,  GA
The Role of Complement in Bystander Hemolysis.

Rick Kapur, MD, PhD
Sanquin Research and Landsteiner Laboratory
Amsterdam,  Netherlands
Complement and TRALI.

Demin Wang, PhD
Versiti Blood Research Institute
Milwaukee,  WI
Role of Complement in HIT.

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Iron and Heme in Stem Cell Maintenance and Erythropoiesis

Saturday, December 9, 2023, 4:00 p.m. - 5:15 p.m. San Diego Convention Center, Room 24

This session was developed by the Scientific Committee on Iron and Heme.

Iron and heme, essential elements for any cell, play a crucial role in shaping the fate of hematopoietic stem cells (HSCs) as they are involved in regulating HSC stemness, proliferation, and differentiation into erythroid cells. On the reverse side, erythropoietic activity is a crucial determinant of body iron homeostasis, as erythroblasts secrete factors that, by targeting the iron regulatory hormone hepcidin, directly control iron recycling and dietary iron absorption to support heme production. This scientific session will highlight recent innovative research that sheds light on the mechanisms regulating the reciprocal relationship between iron/heme and HSC function under physiological and pathological conditions characterized by impaired erythropoiesis and iron overload.  

Dr. Dachuan Zhang will provide an overview of how a microbiota-macrophage-iron axis regulates HSC fate decisions under stress conditions. He will discuss the role of microbiota-derived metabolites in regulating bone marrow macrophage-mediated erythrophagocytosis, which provides emergent and local iron supply for HSC differentiation. 

Dr. Annamaria Aprile will discuss the role of iron on HSC function in ineffective erythropoiesis, focusing on beta-thalassemia as a model for iron-loading anemias. She will discuss the involvement of stromal cells and stress signals such as iron in modulating the functional interactions between HSCs and the bone marrow microenvironment in thalassemia. 

Dr. Léon Kautz will dissect the direct and indirect mechanisms regulating iron distribution to the erythron, the main site of iron utilization. He will provide an updated overview on the functional interaction between the erythron and hepcidin, the master regulator of iron homeostasis, focusing on erythroferrone biology and on the identification of the hepatokine FGL1 as a novel hepcidin regulator in response to anemia and hypoxia.  

Chair:

Laura Silvestri, PhD
San Raffaele Scientific Institute and Vita-Salute Uni.
Milan,  Italy

Speakers:

Dachuan Zhang, PhD
Shanghai Jiao Tong University School of Medicine
Shanghai,  China
Iron and Heme Shape the Hematopoietic Stem Cell (HSC) Fate and the Erythron Function

Annamaria Aprile, PhD
San Raffaele-Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute
Milan,  Italy
Iron and Hematopoietic Stem Cell (HSC) in Ineffective Erythropoiesis

Leon Kautz, PhD
Institut de Recherche en Santé Digestive (IRSD), Université de Toulouse, INSERM
Toulouse,  France
Mechanisms Controlling the Iron Supply to the Erythron and Their Pathophysiological Contributions

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Joint Session: Genome Engineering for Enhanced Blood Cancer Immunotherapy

Sunday, December 10, 2023, 9:30 a.m. - 11: 05 a.m. San Diego Convention Center, Room 6CF

This session was developed by the Scientific Committee on Immunology and Host Defense + Scientific Committee on Transplantation Biology and Cellular Therapies.

Immunotherapy is the core of emerging cancer treatments. This includes a growing number of cellular immunotherapies being pioneered after the success of chimeric antigen receptor (CAR) engineered T cells and hematopoietic cell transplantation. Fundamental to the next generation of advances of cellular immunotherapies is the ability to manipulate immunity via genome engineering. This scientific session will highlight innovative translational strategies that leverage genome engineering to inform fundamental mechanisms to enhance cancer immunity or overcome clinical challenges of classical CAR T cell therapies.

Dr. Carl June will discuss three genome engineering approaches to improve CAR T cell responses. The first explores CRISPR-Cas9-mediated deletion of co-inhibitory CTLA4 in CAR T cells. The second seeks to develop a universal therapy for hematologic malignancies by targeting the pan-leukocyte marker CD45, protected from on-target/off-tumor toxicity through CRISPR adenine base editing. The third addresses the issue of loss of inflammatory effector functions in T cell therapies, including knock out of both Regnase-1 and Roquin-1. 

Dr. Chiara Bonini will discuss how the development of genetic engineering technologies (CAR, transgenic tumor reactive TCR) and genome editing tools have dramatically changed and expanded the landscape of adoptive cellular therapy. This includes both expanding opportunities and new questions:  how to isolate, design, and combine tools to generate the most fit engineered T cells to treat malignant diseases. Optimal strategies will allow immune cells to infiltrate and survive in the tumor microenvironment, recognize relevant tumor antigens, and to persist as memory cells. 

Dr. Dan Kaufman will discuss strategies to utilize natural killer (NK) cells and macrophages to target refractory malignancies. NK cells isolated or derived from peripheral blood, umbilical cord blood or induced pluripotent stem cells (iPSCs) can be engineered to express CARs and modified to improve their anti-tumor activity. Specific approaches include deletion of CISH and TGFbII receptor, or engineered resistance to immunosuppressive drugs. These NK cell and macrophage cellular therapies enable new strategies to enhance innate immune responses to cancer. 

Dr. Alexander Marson will discuss using CRISPR-mediated gene editing in primary human T cells to systematically identify genetic targets that modulate the functions of T cells in contexts ranging from immunosuppression to cancer killing. Development and application of CRISPR-based methodologies such as pooled knock-in screening, CRISPR activation, and CRISPR interference pinpoint the regulatory networks controlling T cell phenotypes and identify synthetic genetic programs to improve T cell activity in cancer, autoimmunity, and infection. 

Co-Chairs:

Todd A Fehniger, MD,PhD
Washington University School of Medicine in St. Louis
Saint Louis,  MO

Carl June, MD
University of Pennsylvania
Philadelphia,  PA

Speakers:

Alexander Marson, MD, PhD
University of California, San Francisco
San Francisco,  CA
Decoding and Rewriting Immune Cells to Advance Immune Responses to Cancer.

Dan S Kaufman, MD, PhD
University of California San Diego
La Jolla,  CA
Engineering Alternative Immune Cells as Blood Cancer Immunotherapy.

Chiara Bonini, MD
IRCCS Ospedale San Raffaele
Milano,  Italy
TCR Engineering of Immune Cells to Enhance Responses to Blood Cancers

Carl June, MD
University of Pennsylvania
Philadelphia,  PA
Applying Genome Engineering to Enhance CAR T Cell Responses to Blood Cancers.

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Joint Session: Lymphomagenesis - What Normal Immunology, Abnormal Immunology, and Genomics Can Teach Us About Lymphoma Biology and Novel Therapeutic Strategies

Saturday, December 9, 2023, 4:00 p.m. - 5:35 p.m. San Diego Convention Center, Ballroom 20AB

This session was developed by the Scientific Committee on Hematopathology and Clinical Laboratory Hematology + Scientific Committee on Lymphoid Neoplasia.

This joint session between the subcommittees on lymphoid neoplasia and hematopathology will investigate four different areas of study that can teach us about how lymphoma develops and provide insights into new or improved therapeutic strategies.

Dr. Aswin Sekar will discuss his work on clonal hematopoiesis and precursor mutations as it relates to the development of lymphoid neoplasms, so-called L-CHP, and what it may teach us about the precursor genetic events that increase one's risk of developing lymphoma.

Dr. Laura Pascqualucci will relate aberrant germinal center expansion with the process of lymphomagenesis in discussing her work related to epigenetic alterations and key genetic mutations that play a role in germinal centers gone wrong.

Dr. Christian Munz is an infectious disease specialist with an expertise in EBV infection and EBV related lymphomagenesis and will discuss what we know about viral oncogenesis and how it can be applied to our understanding on non-viral causes of lymphoma evolution.

Dr. Mandeep Singh studies autoimmunity and has identified lymphoma driver mutations associated with the development of rheumatoid factor autoantibodies and will discuss the intersections between autoimmunity and lymphomagenesis and how the abnormal immune response in autoimmune diseases may be relevant to the development of lymphoid neoplasms and to their therapies.

Co-Chairs:

Parul Bhargava, MD
University of California San Francisco
San Francisco,  CA

Caron A Jacobson, MD, MMSc
Dana-Farber Cancer Institute
Boston,  MA

Speakers:

Aswin Sekar, MD,PhD
Dana-Farber Cancer Institute
Boston,  MA
Mutations in Healthy Humans Associated with Lymphoid Malignancies

Laura Pasqualucci, MD
COLUMBIA UNIVERSITY
New York,  NY
Aberrant Germinal Center Expansion and Lymphomagenesis

Christian Munz, PhD
University of Zurich
Zurich,  Switzerland
Infections and Lymphomagenesis

Mandeep Singh, PhD
Garvan Institute of Medical Research
Darlinghurst/Sydney,  NSW, Australia
Immune Dysregulation and Lymphomagenesis

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Joint Session: Ontogeny and Myeloid Disorders of Childhood

Saturday, December 9, 2023, 4:00 p.m. - 5:35 p.m. Marriott Marquis San Diego Marina, Marriott Grand Ballroom 5-6

This session was developed by the Scientific Committee on Myeloid Biology + Scientific Committee on Stem Cells and Regenerative Medicine.

Blood malignancies and immunodeficiencies arise against a backdrop of normal intrinsic and extrinsic perturbations that blood progenitors face as they transition from fetal to juvenile to adult stages of life. Normal ontogeny can play a critical role in shaping the underlying biology of childhood blood disorders. In this scientific session, we will explore interactions between normal developmental programs and the abnormal programs that contribute to childhood leukemias or immune deficiency. We will first highlight recent advances in our understanding of normal hematopoietic stem and progenitor cell ontogeny. We will then explore how fetal and neonatal developmental programs can shape the biology of a representative early childhood malignancy: myeloid leukemia of Down Syndrome (ML-DS). Finally, we will explore how maternal stress, such as inflammation or infection, can influence childhood immune development. The cutting-edge science presented here will illuminate mechanisms that critically influence health and well-being.  

Dr. Shannon McKinney-Freeman will present an overview of our current understanding of the normal ontogeny of the hematopoietic system during embryogenesis and early life. She will emphasize recent findings that challenge long-held assumptions regarding the developmental origins of hematopoietic progenitors and their transition from embryonic to fetal to adult molecular identities.  

Dr. Jan-Henning Klusmann will describe mechanisms underlying ML-DS, a malignancy that arises exclusively in young children with trisomy 21. ML-DS carry pathogomonic mutations in GATA1, and they evolve from antecedent transient abnormal myelopoiesis, a disorder that occurs in 10-30% of neonates with Down Syndrome. The developmentally restricted nature of this malignancy highlights the critical role for fetal/neonatal programming in its pathogenesis. Dr. Klusmann will discuss how RUNX1 isoform shifting during normal fetal ontogeny can sensitize progenitors to GATA1 mutations. He will also discuss the critical, developmentally restricted roles of miR-125b and ARID3A in ML-DS initiation. 

Dr. Alan Cantor will describe how inherited GATA1 deficiency can predispose to ML-DS-like leukemias with somatically acquired trisomy or tetrasomy 21. He will highlight the significant phenotypic overlap between these leukemias and ML-DS, including early age of onset. The implications of these findings will be discussed, as they relate to age-specific mechanisms of ML-DS.  

Dr. Anna Beaudin will discuss recent findings showing that prenatal inflammation can reprogram fetal hematopoietic progenitor cells, with sustained consequences for postnatal immune function and infection susceptibility. Dr. Beaudin will also highlight new data demonstrating that other types of developmental perturbation, including variation in maternal nutritional status, can program hematopoietic stem cell function into adulthood.

Co-Chairs:

Eirini Papapetrou, MD, PhD
Icahn School of Medicine at Mount Sinai
New York,  NY

Jeffrey Magee, MD,PhD
Washington University School of Medicine
Saint Louis,  MO

Speakers:

Shannon McKinney-Freeman, PhD
St. Jude Children's Research Hospital
Memphis,  TN
Normal Hematopoietic Ontogeny

Jan-Henning Klusmann, MD
Goethe University Frankfurt
Frankfurt,  Germany
Ontogeny and Malignant Disorders of Childhood

Alan B. Cantor, MD, PhD
Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School
Boston,  MA
Ontogeny and Inherited Myeloid Disorders

Anna E Beaudin, PhD
University of Utah
Salt Lake City,  UT
Microenvironmental Contributions to Fetal/Neonatal Blood Development and Diseases

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Mechanisms of Genetic Rescue in Inherited Bone Marrow Failure Syndromes

Saturday, December 9, 2023, 9:30 a.m. - 10: 45 a.m. San Diego Convention Center, Room 7

This session was developed by the Scientific Committee on Bone Marrow Failure.

Somatic genetic rescue in inherited bone marrow failure (BMF) syndromes results in removal or compensation of the germline disease-causing mutation. This often results in clonal hematopoiesis with increased fitness and measurable improvement of hematologic parameters. This phenomenon is becoming increasingly important for i) diagnosis (as it represents a natural functional assay for a given syndrome), ii) therapy stratification (early bone marrow transplantation vs. watchful waiting), and iii) long-term surveillance. It also provides a knowledge base for developing future therapies in these patients. This scientific session will discuss up to date knowledge on the mechanisms of genetic rescue in inherited BMF syndromes. 

Dr. Jean Soulier will present new data on clonal hematopoiesis in Fanconi anemia (FA), a DNA repair disorder with chromosome instability resulting in hematopoietic stem/progenitor cell exhaustion, BMF and high-risk myeloid leukemia. Half of FA patients develop chromosome 1q gain with resulting MDM4 trisomy which downregulates the overactive p53 signaling, which can be later followed by secondary leukemia-driver alterations. Functionally, MDM4 triplication confers greater fitness to murine and human hematopoiesis, rescues inflammatory marrow failure, and drives clonal dominance in FA mouse models. He will also demonstrate how early MDM4-driven downregulation of p53 activation plays a pivotal role in FA clonal evolution.  

Dr. Alyssa Kennedy will discuss clonal hematopoiesis and the specific somatic mutations that occur in the bone marrow of patients with Shwachman-Diamond Syndrome (SDS). SDS is a ribosomopathy caused by biallelic mutations in the SBDS gene. The lack of SDS protein leads to defects in ribosome maturation. Patients with SDS develop clonal hematopoiesis at an early age. The somatic mutations in SDS consist of adaptive mutations - as in EIF6 - or maladaptive mutations in TP53. Dr. Kennedy will discuss the underlying mechanism of clonal expansion in SDS and the implications of clonal hematopoiesis for surveillance.  

Dr. Sushree Sahoo will introduce into the recently discovered SAMD9 and SAMD9L (SAMD9/9L) diseases, hereditary BMF conditions with a propensity for myelodysplasia with monosomy 7. Germline SAMD9/9L mutations are deemed gain-of-function mutations as their overexpression inhibits cellular growth, halts translation, and lead to cell death in a manner that is significantly higher than the wildtype protein. Many patients attain somatic genetic rescue, causing inactivation of mutant alleles and selective clonal hematopoiesis. Dr. Sahoo will elaborate on the clonal trajectories and clinical implications of rescue events in SAMD9/9L and provide an overview of the current understanding of the molecular mechanism by which SAMD9/9L mutants impair hematopoiesis. 

Chair:

Marcin W. Wlodarski, MD, PhD
St. Jude Children's Research Hospital
Memphis,  TN

Speakers:

Jean Soulier, MD
Hôpital Saint-Louis
Paris,  France
Clonal Hematopoiesis and Mosaicism in Fanconi Anemia.

Alyssa Kennedy, MD, PhD
St. Jude Children's Research Hospital
Memphis,  TN
Clonal Hematopoiesis in Shwachman Diamond Syndrome

Sushree S Sahoo, PhD
St. Jude Children's Research Hospital
Memphis,  TN
Somatic Genetic Rescue in SAMD9 and SAMD9L Syndromes

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Mechanistic Role(s) of Neutrophil Extracellular Traps in Thrombosis

Saturday, December 9, 2023, 4:00 p.m. - 5:15 p.m. San Diego Convention Center, Room 31

This session was developed by the Scientific Committee on Thrombosis and Vascular Biology.

A key prothrombotic feature of neutrophils is their ability to release web-like structures composed of DNA filaments coated with histones and granule proteins referred to as neutrophil extracellular traps (NETs). Although NETs have a protective role against pathogens, an uncontrolled and excessive NETs formation within the vasculature contributes to pathological thrombotic disorders. NETs promote vessel occlusion by providing a scaffold for platelets, red blood cells, extracellular vesicles, and procoagulant molecules, such as von Willebrand factor and tissue factor. NET components also enhance coagulation by activating the intrinsic and degrading an inhibitor of the extrinsic coagulation pathway. The talks in this scientific session will highlight the mechanisms that regulate thrombus initiation and propagation, review the role of neutrophils in thrombosis, discuss the crosstalk between NETs and intrinsic coagulation pathway and describe new methods for both imaging and targeting thrombosis. 

Dr. Martinod will discuss the pathological role of NETs in various human diseases. She will emphasize the importance of citrullinated histones, generated during NET formation by the peptidyl arginine deaminase 4 (PAD4), as useful biomarkers of ongoing NET formation. She will summarize studies in animal models showing protective effects of PAD4-deficiency in MPN-driven thrombosis and cardiac fibrosis. Dr. Martinod’s presentation will provide insight into potential therapeutic approaches to inhibiting NETs. 

Dr. Evi Stavrou will present novel insights into the role of neutrophils in in vivo models of thrombosis. While an integral component of the innate immune response, recent evidence supports that unrestricted recruitment and function of activated neutrophils can prolong inflammation and contribute to the development of pathologic conditions including vascular thrombosis. Dr. Stavrou will discuss how disease-specific factors, animal model selection, and specific vascular beds impact neutrophil activities, the signaling pathways they intersect, and how targeting neutrophil components can be exploited for prognostic and therapeutic development against thrombosis. 

Dr. Ioannis Mitroulis will present recent evidence derived from animal models and clinical observations, demonstrating the critical involvement of cells of the myeloid lineage in venous thrombosis. He will provide an overview on immunothrombosis as a mechanism that links the activation of neutrophils and monocytes with thrombotic disorders. His presentation will focus on thrombotic complications associated with hematopoietic malignancies and solid tumors, as well as with infectious and inflammatory disorders including COVID-19. Dr. Mitroulis will also discuss how the inflammatory environment in such disorders reprograms neutrophils and monocytes towards a pro-thrombotic phenotype. 

Chair:

Rafal Pawlinski, PhD
University of North Carolina at Chapel Hill
Chapel Hill,  NC

Speakers:

Kimberly Martinod, PhD
KU, Leuven
Leuven,  Belgium
NETs and Thrombosis in Different Disease States.

Evi X. Stavrou, MD
Case Western Reserve University
Cleveland,  OH
Role of Neutrophils in In Vivo Models of Thrombosis.

Ioannis Mitroulis, MD,PhD
Democritus University of Thrace
Alexandroupolis,  Greece
Role of Immune Cells in the Pathophysiology of Thrombosis.

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Next Generation of Gene-Based Therapies for Bleeding Disorders

Saturday, December 9, 2023, 9:30 a.m. - 10: 45 a.m. San Diego Convention Center, Room 31

This session was developed by the Scientific Committee on Hemostasis.

Gene therapy for bleeding disorders has achieved significant milestones with the recent approval of adeno-associated viral vector-based products for hemophilia B and hemophilia A. While gene therapy for hemophilia remains actively in clinical development, achieving sustained and predictable clotting factor activity sufficient to ameliorate bleeding in all patients remains an unrealized goal. Furthermore, currently pediatric patients and patients with inhibitors to the clotting factor are not eligible for these treatments. Thus, additional optimization is necessary for meeting these gaps to achieve therapeutic benefit for all patients. In addition, gene-based approaches to treat von Willebrand disease have been challenging to develop. This scientific session will highlight research into novel therapeutic approaches for bleeding disorders.  

Dr. Leah Sabin will present a next-generation approach to gene replacement therapy for hemophilia. She will provide an overview of a CRISPR-mediated targeted gene insertion platform that utilizes the Albumin locus to express therapeutic proteins from the liver, and will discuss how the technology has been applied to the development of a potential treatment for hemophilia B.  

Dr. Lindsey George will discuss efforts to engineer Factor VIII to improve the therapeutic effect of hemophilia A gene transfer. Like current hemophilia B gene therapy efforts that universally employ an enhanced hemostatic function Factor IX variant (Factor IX-Padua), hemophilia A gene therapy may similarly be revolutionized by using Factor VIII variants with improved hemostatic function and/or secretion. Dr. George will discuss prior and ongoing basic and translational efforts to rationally design Factor VIII variants for improved, second-generation approaches to hemophilia A gene therapy.  

 Dr. Jeroen Eikenboom studies siRNA-mediated approaches to treat von Willebrand disease (VWD). Current treatment of VWD focuses on increasing circulating von Willebrand factor (VWF) levels by desmopressin or VWF-containing concentrates. However, this approach leaves the production of mutant VWF unhindered. In most cases, VWD is caused by heterozygous missense mutations that have a dominant-negative effect. Selective silencing of expression of this mutant allele would result in the production of normal VWF only and thereby improvement of the bleeding phenotype. The talk will focus on the possibilities of selective inhibition of mutant VWF alleles using siRNAs. 

Chair:

Denise E. Sabatino, PhD
Children's Hospital of Philadelphia
Philadelphia,  PA

Speakers:

Leah Sabin, PhD
Regeneron Pharmaceuticals
New York,  NY
Novel Approaches for Gene-Based Therapies:?Targeted Gene Insertion of Factor 9 as a Potential Durable Treatment for Hemophilia B

Lindsey A. George, MD
The Children's Hospital of Philadelphia
Philadelphia,  PA
Rational Design of Factor VIII Variants for Hemophilia A Gene Therapy

Jeroen Eikenboom, MD,PhD
Leiden Univ. Medical Center
Leiden,  Netherlands
SiRNA Mediated Strategies for Von Willebrand Disease

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Pre- and Post-Thrombus: Risk Factors of Clotting and Post-Thrombosis Syndrome

Monday, December 11, 2023, 10: 30 a.m. - 11: 45 a.m. San Diego Convention Center, Room 31

This session was developed by the Scientific Committee on Blood Disorders in Childhood.

Thrombosis is a severe medical condition that can affect both children and adults. While several genetic risk factors for venous thrombosis are well recognized, only 10-30% of at-risk individuals will ever sustain an event, due to the presence of unidentified modifier genes. This scientific session will highlight research that aims to unravel the effect of genetics, inflammation, and treatment on disease severity including the post-thrombotic syndrome.  

Dr. Jordan Shavit will discuss strategies for detection of modifier genes of known thrombophilic risk factors using the zebrafish model. His group has used genome editing to develop highly penetrant zebrafish models of venous thrombosis, including protein C and antithrombin deficiency. These models have been used to identify new modifiers from: a) high throughput genome-wide mutagenesis screens in zebrafish, and b) validation of loci from genome-wide association studies (GWAS) in human populations.  

Dr. Pavel Davizon-Castillo will discuss the role of inflammation in thrombosis, emphasizing the immunometabolic responses of megakaryocytes and platelets and their contribution to thromboembolism. He will provide an overview of the immunometabolic determinants of platelet function in pediatric diseases. 

Dr. Suzan Williams will discuss post thrombotic syndrome in children.  Risk factors for the subsequent development of post thrombotic syndrome following a deep vein thrombosis, diagnostic tools for identifying post thrombotic syndrome, and current management, which is largely supportive, will be reviewed. There is a need for future development of improved prevention and treatment approaches to reduce the potential long-term morbidity and reduction in health-related quality of life, which can occur as a result of post thrombotic syndrome in children. 

Chair:

Natasha Archer, MD
Dana-Farber/Boston Children's Cancer and Blood Disorder Ctr.
Boston,  MA

Speakers:

Jordan Shavit, MD,PhD
University of Michigan
Ann Arbor,  MI
Genetics of Thrombosis

Pavel Davizon-Castillo, MD
BloodWorks Northwest/University of Washington
Seattle,  WA
The Role of Inflammation in Thrombosis

Suzan Williams, MD
Hospital for Sick Children
Toronto,  ON, Canada
Post-Thrombotic Syndrome

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Single Cell Omics and High Resolution Imaging to Unravel the Role of the Niche in Stress and Ageing Hematopoiesis

Saturday, December 9, 2023, 4:00 p.m. - 5:15 p.m. Marriott Marquis San Diego Marina, Marriott Grand Ballroom 8-9

This session was developed by the Scientific Committee on Hematopoiesis.

Recent developments in imaging and single cell technologies have increased our knowledge on the role of the bone marrow microenvironment for adult hematopoiesis. Similar approaches are now used to investigate the response and communication of the bone marrow niche under stress conditions such as inflammation or ageing. This scientific session will highlight the use of single cell omics and different newly developed imaging technologies to unravel the role of bone marrow niche under inflammation and aging. These stories highlight the importance of stress-induced changes in the composition and supportive role of the microenvironment for the communication with hematopoietic stem cells (HSCs) and the response and recovery of these stem cells upon stress. 

Dr. Tiago Luis will discuss the role of the HSC niche in sensing specific demands in blood cell production and instructing HSCs to re-establish blood cell homeostasis. He will present a new feedback mechanism by which IL-1 secreted by activated platelets, activates the IL-1 signaling pathway in a specific subset of Lepr+IL-1R+ peri-sinusoidal cells. IL-1 signaling in this niche cell compartment is critical to the optimal activation of platelet-biased (Vwf+) HSCs. Dr. Luis will also discuss the dynamics of platelet-biased HSCs and their interactions with the surrounding bone marrow microenvironment, in homeostasis and post platelet depletion, analyzed by intravital imaging of highly pure Hoxb5+Vwf+ HSCs in the mouse calvarium.  

Dr. Maria Carolina Florian will introduce how the bone marrow niche is remodeled upon aging focusing on the alterations of the vasculature and of the arteriolar vessels. She will show by 3D high resolution imaging that in aged mice the HSCs with the highest regenerative capacity have divided the less over time, are mostly polar for H4K16ac (epigenetic polarity) and are exclusively located next to bone marrow sinusoidal endothelial cells expressing the Notch ligand Jag2. Dr. Florian will also discuss data revealing that endothelial Jag2 regulates HSCs function upon aging through Notch signaling activation, which depends on HSC localization. 

Dr. Daniel Lucas-Alcaraz will discuss new strategies to emerge stepwise hematopoiesis across the skeleton. He will provide an overview of the anatomy of normal and stress blood cell production highlighting novel patterns of progenitor movement and behavior and demonstrating that terminal differentiation for each blood lineage occurs in distinct, specialized, vascular niches. He will link hematopoietic plasticity to lineage- and insult-specific changes in the output of the production sites for each lineage. 

Chair:

Keisuke Ito, MD,PhD
Albert Einstein College of Medicine
Bronx,  NY

Speakers:

Tiago C. Luis, PhD
Imperial College London
London,  United Kingdom
Niche Regulation of HSCs in Homeostasis and Emergency Hematopoiesis

Maria Carolina Florian, PhD
The Catalan Institution for Research and Advanced Studies (ICREA), The Bellvitge Institute for Biomedical Research (IDIBELL)
Barcelona,  Spain
Ageing in the Hematopoietic Stem Cells Niche

Daniel Lucas-Alcaraz, PhD
Cincinnati Childrens' Medical Center
Cincinnati,  OH
High Resolution Imaging to Visualize Changes in the Bone Marrow Niche

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Spatial Genomic & Epigenomic Profiling in Hematology

Saturday, December 9, 2023, 2:00 p.m. - 3:15 p.m. Marriott Marquis San Diego Marina, Marriott Grand Ballroom 8-9

This session was developed by the Scientific Committee on Epigenetics and Genomics.

Single cell approaches to analyzing genomic and epigenomic regulation have revolutionized our understanding of cell types, plasticity, development, and malignancy. While single-cell analysis has begun to elucidate the cellular components that participate in tissue function and dysfunction; interactions -- and their spatial variation across tissue structures--remain challenging to explore. Recent advances in technologies enabling spatial profiling are now allowing for the understanding of these cellular interactions in situ at an unprecedented level of detail. This scientific session will encompass an overview of novel technologies, applications to understanding clonal heterogeneity in tissues, spatial and temporal regulatory mechanism that shape cellular identity and heterogeneity, and high-resolution mapping of chromatin in situ.  

Dr. Fei Chen will discuss a toolbox for single-cell spatial genomics. He will provide an overview of recent advances in the technology of single cell sequencing in the context of tissues. Specifically, he will describe advances in situ and single cell transcriptomic sequencing tools which aim to capture both the spatial context of cells within tissues and their gene expression programs. Dr. Chen will provide an overview of a novel approach for single-cell spatial genomics, as well as applications in immune receptor profiling, cell-cell interactions in the tumor microenvironment, and in situ genetic alterations.  

Dr. Elham Azizi will discuss spatial and temporal mechanisms that underlie the leukemic microenvironment. Using longitudinal single cell transcriptomic and spatial protein imaging data from patients with relapsed acute myeloid leukemia and chronic myeloid leukemia following hematopoietic Stem Cell Transplantation., Dr. Azizi has designed and implemented computational frameworks for integration and interpretation of this data and a novel machine learning tool for time-resolved prediction of cell-cell interactions. In doing so, Dr. Azizi’s work has revealed disease-specific coordinated immune networks associated with the inhibition of leukemia cells in responder patients, which can be leveraged in the development of next-generation therapeutic strategies.  

Dr. Rong Fan will discuss novel methods and technologies for profiling of proteins, transcriptomes, and chromatin at the single-cell level in tissues. While single-cell methods in dissociated tissue samples provide remarkable insights into the identity and function of cells and have been successful in identifying new cell types, spatial multi-omics are predicted to provide novel insights. Dr. Fan will discuss approaches to profile proteins, whole transcriptomes, chromatin accessibility and regulation in situ. He will also highlight potential applications to understanding spatially resolved cellular function in hematopoietic and lymphoid tissues. 

Chair:

Dinesh S. Rao, MD, PhD
UCLA
Los Angeles,  CA

Speakers:

Fei Chen, PhD
Broad Institute of MIT and Harvard
Cambridge,  MA
Spatial Mapping of immune Cells & Clonal Heterogeneity in Tissues

Elham Azizi
Columbia University
New York,  NY
Understanding the Spatial-contextual Regulatory Mechanisms That Shape Cellular Identity and Heterogeneity

Rong Fan, PhD
Yale University
New Haven,  CT
Spatial Mapping of Chromatin and Proteomes

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The Evolution of Multiple Myeloma: From Inside-Out

Saturday, December 9, 2023, 9:30 a.m. - 10: 45 a.m. Manchester Grand Hyatt San Diego, Grand Hall C

This session was developed by the Scientific Committee on Plasma Cell Neoplasia.

While the number of therapies now available for Multiple Myeloma (MM) has grown tremendously, our understanding of the disease is still evolving. We now know that there are intricacies in even the most classic of signaling pathways, for example as related to myc signaling. In addition, we have gained further understanding of the impact of non-traditional nucleotides such as lncRNA and miRNA. Even more interesting has been a clearer picture of signaling outside of the plasma cell, not just within it. While we have long understood the importance of the immune microenvironment, we now also recognize numerous nonimmune factors in the bone marrow microenvironment which can modulate the disease. This session will describe cutting edge findings as they relate to some of the known and lesser-known factors in myelomagenesis.  

Dr. Marta Chesi will summarize our current knowledge on the role of MYC in myeloma pathogenesis, with a particular focus on MYC involvement in the transition from stable monoclonal gammopathy to progressive MM disease in mice and humans. She will also describe the complexity of genomic events leading to both cis and trans activation of MYC in myeloma, as well as therapeutic approaches to target MYC. 

Dr. Eugenio Morelli will discuss the emerging roles of non-coding RNAs in multiple myeloma. He will provide an overview of the recent studies dissecting the clinically relevant noncoding transcriptome in MM and the use of these molecules as biomarkers and predictors of outcomes. Dr. Morelli will present ongoing investigations leveraging the use of innovative RNA-targeting CRISPR technologies to discover the tumor-promoting functions of non-coding RNAs. He will highlight important roles for these molecules in the pathobiology of MM, such as the regulation of c-MYC transcriptional activity. Finally, Dr. Morelli will also convey a provocative scenario whereby the use of optimized antisense oligonucleotides or RNA-targeting small molecules will unlock the therapeutic potential of non-coding RNAs, turning them into valuable targets to cure MM.  

Dr.Tom Cupedo will discuss the cellular interactions driving a tumor-supportive bone marrow environment in patients with multiple myeloma. He will provide an overview of the inflammatory alterations in the bone marrow stromal cell niche for malignant plasma cells, and link changes to activation of immune cells and presence of inflammatory proteins. First-line treatment significantly impacts pro-tumor bone marrow inflammation but fails to fully normalize the plasma cell niche. The impact of these findings on myeloma pathobiology will be discussed.  

Chair:

Nina Shah, MD
AstraZeneca
South San Francisco,  CA

Speakers:

Marta Chesi, PhD
Mayo Clinic
Scottsdale,  AZ
The Big Myc – What We Know About Myc Signaling in Myelomagenesis

Eugenio Morelli, MD
Dana-Farber Cancer Institute
Boston,  MA
Alternate Code: The Role of Non-Coding RNAs in Multiple Myelmoa

Tom Cupedo, PhD
Erasmus University Medical Center
Rotterdam,  Netherlands
Fertile Soil: The Contribution of the Non-Immune Microenvironment in the Development of Multiple Myeloma

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The Long Non-Coding Road, RNA and Signaling, and Regulation of Globin Gene Expression.

Saturday, December 9, 2023, 4:00 p.m. - 5:15 p.m. San Diego Convention Center, Room 25

This session was developed by the Scientific Committee on Red Cell Biology.

Red blood cells may play a single note (hemoglobin, hemoglobin, hemoglobin), but this conceals an orchestra of complex molecular regulation that has engaged scientists for over 80 years. Progress in this field has informed our understanding of many molecular processes, including the ‘louder’ more obvious orchestral elements (i.e., regulatory DNA [enhancers, promoters, etc.], transcription factors, and chromatin structure). This session will highlight recent remarkable insights about ‘quieter’ more subtle regulators of globin gene expression, which are essential to a fuller understanding of human red blood cell biology and disease. Knowledge gained about the molecular regulation of erythropoiesis will continue to transform therapy in globin gene disorders, such as Sickle Cell Disease and ß-Thalassemia.  

Dr. Mitchell Weiss will discuss how hypoxia inducible factor 1 (HIF1) regulates red blood cell fetal hemoglobin (HbF, a2g2) expression by binding to cognate DNA elements in the BGLT3 long noncoding RNA gene located 2.7 kb downstream of the g-globin genes (HBG1 and HBG2). These findings link globin gene regulation with canonical hypoxia adaptation, provide a mechanism for HbF induction during increased erythropoietic demand (“stress erythropoiesis”), and suggest a new therapeutic approach for Sickle Cell Disease and ß-Thalassemia.   

Dr. Ann Dean will discuss the role of long non-coding RNAs (lncRNAs) in erythroid differentiation. LncRNAs are defined as RNA transcripts of longer than 200 nucleotides, without potential to code for a polypeptide. Nuclear lncRNAs have been found to regulate gene expression in almost all aspects, from transcription to translation, by diverse mechanisms.  Dr. Dean will describe an antisense lncRNA transcribed opposite to the GATA2 gene that regulates numerous erythroid genes by interacting with erythroid transcription factors. She will also document a lncRNA transcribed from one of the enhancers of the Myb gene, an enhancer RNA or eRNA, that interacts with the co-regulator complex MLL1 to regulated Myb transcription. Loss of either of these lncRNAs results in elevated HBG1/HBG2 transcription, highlighting the potential of lncRNA manipulation as a therapeutic approach to Sickle Cell Disease and ß-Thalassemia.  

Dr. Gerd Blobel will summarize recent work that made use of advanced CRISPR screening tools to gain new insights into mechanisms that impinge on the switch from fetal to adult hemoglobin production in human erythroid cells. This includes new regulatory factors that act directly on the globin gene cluster as well as those that function via intermediates. Dr. Blobel will discuss the broader ramifications of this work with respect to fundamental mechanisms of developmental gene expression control and highlight the implications for new therapeutic approaches for the treatment of hemoglobinopathies.   

Chair:

Jane A. Little, MD
UNC-Chapel Hill
Chapel Hill,  NC

Speakers:

Mitchell Weiss, MD, PhD
St. Jude Children's Research Hospital
Memphis,  TN
Understanding Fetal Hgb Regulation: HIF1alpha and LNC RNA

Ann Dean, PhD
National Institutes of Health
Bethesda,  MD
Understanding Fetal Hgb Regulation: LNC RNA

Gerd A. Blobel, MD, PhD
Children's Hospital of Philadelphia
Philadelphia,  PA
Mechanisms of Developmental Globin Gene Expression Control Revealed via Functional CRISPR Screens