The EHA Research Roadmap: Normal Hematopoiesis
HemaSphere, vol. 5, pp. e669
Abstract
In 2016, the European Hematology Association (EHA) published the EHA Roadmap for European Hematology Research1 aiming to highlight achievements in the diagnostics and treatment of blood disorders, and to better inform European policy makers and other stakeholders about the urgent clinical and scientific needs and priorities in the field of hematology. Each section was coordinated by 1–2 section editors who were leading international experts in the field. In the 5 years that have followed, advances in the field of hematology have been plentiful. As such, EHA is pleased to present an updated Research Roadmap, now including 11 sections, each of which will be published separately. The updated EHA Research Roadmap identifies the most urgent priorities in hematology research and clinical science, therefore supporting a more informed, focused, and ideally a more funded future for European hematology research. The 11 EHA Research Roadmap sections include Normal Hematopoiesis; Malignant Lymphoid Diseases; Malignant Myeloid Diseases; Anemias and Related Diseases; Platelet Disorders; Blood Coagulation and Hemostatic Disorders; Transfusion Medicine; Infections in Hematology; Hematopoietic Stem Cell Transplantation; CAR-T and Other Cell-based Immune Therapies; and Gene Therapy. Fundamental as well as translational research has been critically important to get us where we are today in the field of hematopoiesis studies. Still, many questions remain. Among many others, these include: How do (epi)genetic aberrations cause hematologic malignancies, and how can we use these insights to develop better therapeutic strategies? It is now being realized that clonal heterogeneity exists in many hematologic cancers and possibly even within the normal hematopoietic stem cell (HSC) compartment, but how does this affect disease development and current treatment options remains largely unknown. In contrast to adult life, HSCs are rapidly expanding during embryogenesis, so can we unravel those mechanisms and apply them to in vitro HSC expansion protocols for clinical use? A thorough understanding of embryonic versus adult hematopoiesis might also help to better understand differences between childhood and adult hematologic malignancies. Reprogramming now allows the generation of patient-specific iPSCs, but the generation of fully functional HSCs from these cells is still rather challenging, can we improve this? We live in a continuously aging society, but how does HSC aging actually affect health and disease? Within this section, we provide an overview of the current status of the field and an outlook on where future research should be headed (Fig. 1). We firmly believe that combining fundamental and translational research will result in not only a better understanding of the hematopoietic system but also the development of better therapeutic approaches for hematologic malignancies, many of which are still difficult to treat.Figure 1.: Overview of the current field and an outlook on where future research should be headed.Erythropoiesis The major cell type in blood is the red blood cell (RBC). RBCs transport oxygen from the lungs to other parts of the body. RBCs are formed during a process called erythropoiesis. This includes the initial specification of HSCs during embryogenesis and the decision of HSCs to contribute to the erythroid lineage.2 About a third of the world’s population has some form of anemia. Acquired anemias are often related to iron deficiency or to systemic disorders such as chronic inflammation. Inherited anemias affect erythropoiesis by diverse mechanisms, such as insufficient hemoglobin (Hb) production (thalassemias), pathological Hb variants (sickle cell disease), defects in membrane proteins or metabolic enzymes (hemolytic anemias), impaired ribosome biogenesis (Diamond Blackfan anemia), and DNA repair defects (Fanconi anemia). Activating JAK2 kinase mutations cause excess RBC production (polycytemia vera). The physiological and molecular mechanisms underlying RBC disorders are still incompletely understood, hampering the development of new treatments. Historically, research of hematopoiesis has driven novel biological concepts, owing to the accessibility of hematopoietic cells for molecular and functional analyses. Early European contributions include the Nobel Prize-winning discovery of the structure of Hb3 and understanding the epidemiology of inherited anemias, leading to implementation of prenatal diagnostic programs.4 Additional European contributions include determining the origin of HSCs, the transcriptional circuitry underlying erythropoiesis, the role of iron metabolism, and DNA sequences driving Hb expression which are now applied in gene therapy. A database dedicated to erythroid disorders has been established.5 Translational research has resulted in optimized stem cell transplantation protocols, magnetic resonance imaging for monitoring of iron overload, improved iron chelation therapies, and targeted inhibition of signaling pathways under (pre)leukemic conditions. Previous research has laid the foundation from which understanding erythropoiesis will be extended. For instance, single cell analysis allows hierarchical relationships between cells to be determined and the impact of cell–cell interactions and signaling cascades to be unraveled. The protocols developed will be quickly translated to clinical applications, as demonstrated by CRISPR-mediated gene editing.6 The goal is to apply this deep understanding of erythropoiesis to improve diagnosis, prognosis, and treatment of patients with RBC conditions. The fundamental understanding of erythropoiesis will have direct impact on medical care of patients with RBC conditions. First, improved diagnosis will lead clinicians to better-informed decisions on disease management. Second, novel curative treatments will be developed, such as those involving gene correction/addition and drugs targeting specific signaling pathways. Third, in vitro generation of RBCs will bring guaranteed disease-free transfusion units to the clinic. Finally, fundamental insights in erythropoiesis will continue to facilitate discoveries in other fields of medicine, leading to better clinical care. Myelopoiesis The body´s immediate defense against invading microorganisms is orchestrated by myeloid effector cells of the innate immune system including granulocytes, monocytes/macrophages, dendritic cells, and rare mast cells. These cells are generally short-lived, and require life-long replenishment by HSCs and their progeny, which gradually transit along their differentiation trajectories and ultimately become highly specialized myeloid effector cells. This complex process, referred to as myelopoiesis, is tightly regulated by growth factors, epigenetic and transcriptional regulators, which coordinate early lineage-specification, cell cycle exit, and terminal differentiation. Consequently, genetic aberrations of key regulators of myeloid differentiation programs have been causally linked to the majority of myeloid diseases such as acute myeloid leukemias (AMLs), myeloid dysplastic syndromes and proliferative neoplasms (MDSs/MPNs), and severe congenital as well as cyclic neutropenia. Hence, in the context of disease, functional characterization of myeloid regulators during steady-state hematopoiesis and infections at both the molecular and system levels is pivotal to understand (1) the biology of myeloid effector cells and their role in innate immune defense and (2) how genetic aberrations affect normal myelopoiesis and cause myeloid disease. For more than 2 decades, European scientists have contributed substantially to the understanding of myelopoeisis as highlighted in the 2016 EHA roadmap for European Hematology Research.1 Since then, the European research community has continued this endeavor with a particular focus on myeloid regulators and networks in health and disease, and the of characterization of novel myeloid differentiation trajectories in the hematopoietic hierarchy. The latter is exemplified by a selection of recent key European achievements: (1) Paul et al7 conducted a seminal single-cell transcriptomics study highlighting that commitment toward specific myeloid lineages is a very early event during hematopoiesis, which is not linked to transitional stages of differentiation via progenitors with multi- and bi-lineage potential, as described in the “classic” models of hematopoiesis. (2) European research consortia have pioneered the mapping of mutational landscapes and aberrant regulatory networks of several myeloid diseases, leading to the identification of novel myeloid regulators, and the development of knowledge bank tools allowing for prognostication and guidance of therapeutic stratification of patients with myeloid diseases.8,9 (3) Transcriptomics studies comparing identical normal and malignant myeloid progenitors have mapped gene expression signatures of disease states in patients, which reflect aberrant signaling pathway activities that contribute to dissect disease biology, and are both prognostic relevant and druggable by novel therapeutic modalities.10–12 The advent of novel comprehensive omics technologies such as single-cell RNA-seq, single-cell ATAC-seq, ChIP-seq analyses of transcriptional and epigenetic regulators, and more recently single-cell proteomics allows to map the phenotypic cellular states of the myeloid differentiation landscape in health and disease, at a hitherto unprecedent resolution. We propose a coordinated European effort that will develop and apply standards for comprehensive single cell omics analyses and establish a Pan-European “reference” single cell library of myeloid cells in health and disease. Ultimately, this single-cell “reference” library will improve our understanding of normal myeloid differentiation (and hematopoiesis in general) and innate immune defense at the system level but also how genetic aberrations of myeloid regulators cause perturbations of normal cellular states can lead to myeloid disease, and how these states can be targeted by novel therapeutic approaches and modalities. A coordinated European effort involving basic and clinical researchers including bioinformaticians is required to achieve the following key aims of the proposed research program: Establishment of a European expert group that will discuss, and continuously for single-cell omics analyses of and blood cells in and myeloid cells in These should include of normal and blood cells, omics protocols and and the development of for single cells omics and clinical of European that will and of and blood from and patients for single cell omics analyses. of specialized European for single-cell omics analysis of and blood cells to the single-cell omics by the expert of a European for and analysis of single cell omics to a “reference” single-cell omics library of normal and cells from and patients with myeloid disease. the should develop allowing researchers and clinicians to and single-cell omics with their including those from patients with myeloid diseases in clinical The proposed research conducted by a European effort will a comprehensive single-cell omics library of myeloid differentiation in health and disease. The single cells library a most for the research as can be in as a of how expression and of or signaling pathways during normal myeloid differentiation and are by genetic aberrations in myeloid this will have impact on European clinical research programs and aiming at (1) novel diagnostic for improved prognostication and (2) therapeutic for of patients with and other rare myeloid is the differentiation process that to This is a cell biology system from the of their the in the blood Platelet production is both regulated by the and The of is on a called which the is by and disorders that factors, signaling and the and The treatments of include and transfusion from but novel approaches are European researchers have a role in the understanding of the of both at the cellular and level and have developed biology advances have been the 5 years by the European pathways of commitment have been from a HSC a major role in and the by a hierarchical pathway an The of in the that lead to a production by an between and dendritic cells was also is not the to as be by in and membrane in both and of 2 in and that is with the of at combining cell from and these new has the in vitro production for transfusion In the development of has an in production of functional from and hematopoietic The major that require research and include: of commitment and differentiation from The new on single cells allowing to study accessibility and as well as DNA with cell biology to understand the mechanisms of and It also to understand the will be to the of and the of is that at and are in How these mechanisms are and how contribute to the and production still remains to be These approaches also provide in the of differentiation and which to of and is that are to and that in steady-state and pathological conditions. are in the immune and this is important to the by the of which is in the and immune The understanding of the molecular of differentiation as well as of production have important clinical understanding disorders new technologies for production in and the identification of new to production in Lymphoid development is by the most complex differentiation process within the hematopoietic of the progenitors and cells rapidly or effector differentiation of the and with of cell or and of in and cells that the and the In this section, we will focus on the initial of differentiation a field in which European have a research studies in the field should lead to a better of the and of the differentiation recent advances in genetic models and approaches at single-cell have largely studies on analyses of recent are still major in our knowledge of the molecular driving development It remains difficult to differentiation with the models of A of current models of development is that do not the between cell that between or cell and at the origin of heterogeneity cell These are the more important that are to be in myeloid development for development of models of differentiation is to and transcriptional approaches with recently developed analyses that for of interactions at the is well than in the studies to identification of or which are now referred but the status of these remains relationships with recently described early progenitors also to be In development studies in should focus on the of clonal of A should also be to approaches that will to from regulatory the development future models of development will to in production in to in production are on progenitors are by in in the field will be to understand the differences in the of versus cell leukemias to therapeutic to cell in disease and Hematopoietic stem cells HSCs were the adult stem cells to their the clinic. HSCs are as a role in adult stem cell their very and clinical many of basic HSC biology approaches to even or their more cellular in the clinic. we the most recent advances in the field of stem cell research in the years and proposed new research that will to be to and the impact of the use of HSCs in the clinic. HSC and of HSC The of stem and cells to steady-state blood has been recently a of recent studies from single-cell analysis have also the by which differentiation These of hematopoiesis have for our understanding of adult stem cell most of these have been in and in most of the new on which have on related cell studies are to HSC heterogeneity and their cell decision both at and under that will to be is to the of the of HSC and their differentiation. 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In knowledge of these should quickly the toward generation of HSCs for therapeutic cells is critically regulated by cells that the production of blood and immune cells to the These cells the hematopoietic It is that of hematopoietic cells, and The of these networks is by the of heterogeneity stem cells and their single-cell have to functional studies will be in the future for the of cells in immune and the specific of HSCs and their the hierarchical stem cell system in the to understanding how other European research has the cellular and of have been developed to gene networks in and studies will be to the specific and of the role of in European research has demonstrated a key role for in the and of a of neoplasms or from cells signaling on of chronic from is required for the of normal and the to the of acute the growth of or in Finally, from and cells from by and targeting mechanisms of and will be key to in hematopoietic the 5 European research has that HSC for from blood and transplantation help the to normal hematopoiesis by or iron in the of and the of in gene with and of of in immune and systemic disease have a impact on immune cells, therapeutic in disorders or disease, and the of research on the and treatment of systemic such as and research in the hematopoietic and other stem cell provide new to and hematopoietic diseases, immune and As a result of this to be the with the of clinical networks a of hematopoietic cell lineages is critically on cell at the stem and level within the hematopoietic hierarchy. These are at the single-cell level the of signaling pathways with the The latter is driven by networks of transcriptional and epigenetic regulators that in a and can form with on and cellular These establish cell transcriptional and epigenetic programs and cells a particular hematopoietic European researchers have contributed to the identification and characterization of networks and in normal and aberrant In have many of these analyses toward in hematopoietic cells from and of these European researchers have been at the of epigenetic a research of the European which has a of on this in the Cell These many new insights the of with to establish epigenetic that cell type but also to the that can still be about how blood cell develop and how we their activities to or disease. This will require a effort to better understand regulatory networks in both normal hematopoiesis and disease and will be only between and in transcriptional and epigenetic regulators are some of the most mutations in hematologic malignancies. that these proteins as regulatory will be important to an understanding of the malignant as a of regulatory Research on the as well as of and on how these the and and epigenetic should be in disease development have been many that the functional of blood cell and cells within are still not These are by the in which the cells the of and and and other In has become that not only the immune system potential, but that also cells of the innate immune system can be and are on and present to cells of the hematopoietic system in disease and from comprehensive on single-cell and analysis of is models to be for by to the between the factors, epigenetic and the of hematologic stem stem cells stem cells including embryonic stem cells and a of cells for from to of the most of the stem cell field is the in vitro of cell in the for therapeutic A comprehensive understanding of the molecular and cellular leading to blood cell and is of to this the 5 European researchers have seminal contributions to several in this research field. embryonic hematopoiesis and have even our understanding of potential, cellular and molecular in blood cell has to a of at population and single-cell These the of cell cycle as a of demonstrated the generation of hematopoietic stem cells from and highlighted gene regulatory driving blood cell these studies have the of blood cell generation how cells are to their in Reprogramming and have at the of European protocols have been for the generation of blood cell including and both direct of and of cells were progenitors were studies have the molecular mechanisms of and their in and epigenetic have demonstrated the of in vitro cell in cell granulocytes, and were approaches from of and of differentiation protocols, to studies have the of these in cell disease For were to improve or from acute the 5 were on the of in vitro of cell for therapeutic these will be the from cell to protocols and clinical The fundamental research on hematopoietic specification to important the 5 but the generation of in vitro hematopoietic stem cells remains this scientific is still the clinical research policy priorities is the mechanisms by which (epi)genetic cause malignancies. A thorough understanding of embryonic versus adult hematopoiesis will help to better understand differences between childhood and adult hematologic malignancies. the generation of patient-specific and the generation of fully functional HSCs is understanding of normal and malignant hematopoiesis via fundamental research is to to the and develop more for malignancies. is a for and is a for and of from from Research from from from was by a clinical research and a from the for Stem Cell and by from the for Research the with a to and research from the other have of to
Authors 8
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Thierry Jaffredo corresponding
Sorbonne Université · Laboratoire de Biologie du Développement · Institut de Biologie Paris-Seine
Affiliation as printed
Sorbonne Université, Institut de Biologie Paris Seine, Laboratoire de Biologie du Développement/UMR7622, Paris, France
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Affiliation as printed
The Francis Crick Institute, London, United Kingdom
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Inserm · École Pratique des Hautes Études · Université Paris Cité · Université Paris Sciences et Lettres · HIPI - Immunologie humaine, physiopathologie et immunithérapie · Institut de recherche Saint-Louis
Affiliation as printed
INSERM U976, Universite de Paris, Ecole Pratique des Hautes Etudes/PSL Research University, Institut de Recherche Saint Louis, France
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Sorbonne Université · Laboratoire de Biologie du Développement · Institut de Biologie Paris-Seine
Affiliation as printed
Sorbonne Université, Institut de Biologie Paris Seine, Laboratoire de Biologie du Développement/UMR7622, Paris, France
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Sorbonne Université · Laboratoire de Biologie du Développement · Institut de Biologie Paris-Seine
Affiliation as printed
Sorbonne Université, Institut de Biologie Paris Seine, Laboratoire de Biologie du Développement/UMR7622, Paris, France
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Université Paris Cité · Institut des Maladies Génétiques Imagine
Affiliation as printed
Department of Hematology and Laboratory of Physiopathology and Treatment of Blood Disorders, Hôpital Necker, Imagine institute, University of Paris, France
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Affiliation as printed
Gustave Roussy, Villejuif, France
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Sorbonne Université · Laboratoire de Biologie du Développement · Institut de Biologie Paris-Seine
Affiliation as printed
Sorbonne Université, Institut de Biologie Paris Seine, Laboratoire de Biologie du Développement/UMR7622, Paris, France
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