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List ofcontributors
https://t.me/med1917
Sara Ali
Haematopoietic Stem Cell Laboratory, The Francis Crick
Institute, London, United Kingdom
David Avigan
Division of Hematology Oncology, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston,
Massachusetts, United States
Jodie L. Babitt
Massachusetts General Hospital, Harvard Medical School,
Boston, Massachusetts, United States
Mohsin Badat
The Laboratory of Gene Regulation, MRC Weatherall
Institute of Molecular Medicine, University of Oxford,
Oxford, UnitedKingdom
Luciano Baronciani
Angelo Bianchi Bonomi Hemophilia and Thrombosis
Center, Foundation IRCCS Ca’Granda Ospedale Maggiore
Policlinico, Milan, Italy
Kenneth J. Clemetson
University of Berne, Theodor Kocher Institute, Berne,
Switzerland
Björn Dahlbäck
Department of Translational Medicine, Lund University,
University Hospital, Malmö, Sweden
Alexey Danilov
Department of Hematology and Hematopoietic Stem Cell
Transplant, City of Hope National Medical Center, Duarte,
California, United States
Francesco Dazzi
School of Cancer Sciences, King’s College Hospital, London
Carla Dinardo
University of São Paulo, São Paulo, Brazil
William E. Evans
Pharmacy and Pharmaceutical Sciences Department,
StJude Children’s Research Hospital, Memphis, Tennessee,
United States
Colin Brown
Histocompatibility and Immunogenetics Laboratory NHS
Blood and Transplant, Colindale, London,
King’s College London, Faculty of Life Sciences & Medicine,
London, United Kingdom
Dominique Bonnet
Haematopoietic Stem Cell Laboratory, The Francis Crick
Institute, London, United Kingdom
Winnie Chong
Histocompatibility and Immunogenetics Service Development Laboratory, NHS Blood and Transplant, London,
UnitedKingdom
United Kingdom
Bita Fakhri
Division of Hematology, Department of Medicine, Stanford
University, Palo Alto, California, United States
Jude Franklin
Department of Pathology, Case Western Reserve University,
Cleveland, Ohio, United States
Tomas Ganz
Department of Medicine, David Geffen School of Medicine
at UCLA, Los Angeles, California, United States
Keith Gomez
Haemophilia Centre and Thrombosis Unit, Royal Free
London NHS Foundation Trust, London, United Kingdom
x List ofcontributors
https://t.me/med1917
Wilson I. Gonsalves
Division of Hematology, Mayo Clinic, Rochester, Minnesota,
United States
Torsten Haferlach
MLL Munich Leukemia Laboratory, Munich, Germany
Amye M. Harrigan
Department of Medicine, Division of Hematology, QEII
Health Sciences Centre, Dalhousie University, Halifax, NS,
Canada
Douglas Higgs
The Laboratory of Gene Regulation, MRC Weatherall
Institute of Molecular Medicine, University of Oxford,
Oxford, United Kingdom
Andreas Hillarp
Department of Medical Biochemistry, Oslo University
Hospital, Oslo, Norway
Eric D. Hsi
Department of Pathology, Wake Forest University,
Winston- Salem North Carolina, United States
Shunsuke Kimura
Department of Pathology, Hematological Malignancies
Program, St. Jude Children’s Research Hospital, Memphis,
Tennessee, United States
Pramila Krishnamurthy
King’s College Hospital, London
Hillard M. Lazarus
Department of Medicine, Case Western Reserve University
School of Medicine, Cleveland, Ohio, United States
Lucio Luzzatto
Department of Haematology and Blood Transfusion, Muhimbili
University College of Health Sciences, Dar- es- Salaam, Tanzania
Dina Mahdi
Department of Haematology, University College Hospitals
London, London, United Kingdom
Chad M. McCall
Carolinas Pathology Group, Charlotte, North Carolina,
United States
Giovanni Insuasti- Beltran
Department of Pathology, Wake Forest University,
Winston- Salem North Carolina, United States
Deena Iskander
Centre for Haematology, Department of Immunology and
Inflammation, Imperial College London, Hammersmith
Hospital, London, United Kingdom
Elias Jabbour
Department of Leukemia, University of Texas M.D. Anderson
Cancer Center, Houston, Texas, United States
Zachary Jackson
Department of Pathology, Case Western Reserve University,
Cleveland, Ohio, United States
Leo Kager
St Anna Children’s Hospital, St. Anna Children’s Cancer
Research Institute, Medical University Vienna, Vienna, Austria
Hagop Kantarjian
Department of Leukemia, University of Texas M.D. Anderson
Cancer Center, Houston, Texas, United States
William M. McKillop
Department of Pediatrics, Medical College of Wisconsin,
Milwaukee, Wisconsin, United States
Donal P. McLornan
Department of Haematology, University College Hospitals
London, London, United Kingdom
Jeffrey A. Medin
Departments of Pediatrics and Biochemistry, Medical
College of Wisconsin, Milwaukee, Wisconsin, United States
Charles G. Mullighan
Department of Pathology, Hematological Malignancies
Program, St. Jude Children’s Research Hospital, Memphis,
Tennessee, United States
Elizabeta Nemeth
Department of Medicine, David Geffen School of Medicine
at UCLA, Los Angeles, California, United States
Susan O’Brien
University of California at Irvine, Irvine, California,
UnitedStates
Anastasios Karadimitris
Department of Haematology and Blood Transfusion,
Muhimbili University College of Health Sciences,
Dar- es- Salaam, Tanzania
Prateek Pophali
Division of Hematology Oncology, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston,
Massachusetts, United States
List ofcontributors xi
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Victoria Potter
King’s College Hospital, London
Drew Provan
Centre for Haematology, Blizard Institute, Barts & The
London School of Medicine & Dentistry, Queen Mary
University of London, London, United Kingdom
Christopher Saunders
Serviço de Hematologia, Hospital Santo António dos
Capuchos, Centro Hospitalar e Universitário Lisboa Central,
Lisboa, Portugal
David T. Scadden
Department of Stem Cell and Regenerative Biology, Harvard
Stem Cell Institute, Harvard University and Center for
Regenerative Medicine, Boston, Massachusetts, United States
Christian Scharenberg
Department of Hematology, Skaraborgs Hospital Skövde,
Skövde, Sweden
Omid Seidizadeh
Angelo Bianchi Bonomi Hemophilia and Thrombosis
Center, Foundation IRCCS Ca’Granda Ospedale Maggiore
Policlinico, Milan, Italy
Department of Pathophysiology and Transplantation,
Università degli Studi di Milano, Milan, Italy
John W. Semple
Division of Hematology and Transfusion Medicine, Lund
University, Lund, Sweden
Clinical Immunology and Transfusion Medicine, Office of
Medical Services, Region Skåne, Lund, Sweden
Jessica Spiers
Department of Haematology, University College Hospitals
London, London, United Kingdom
Jonathan S. Stamler
Harrington Discovery Institute and Institute of Transformative Molecular Medicine, University Hospitals Cleveland
Medical Center and Case Western Reserve University,
Cleveland Ohio, United States
Marilyn J. Telen
Department of Medicine, Division of Hematology and Duke
Comprehensive Sickle Cell Center, Duke University Medical
Center, Durham, North Carolina, United States
Louise Tilley
International Blood Group Reference Laboratory, NHS
Blood and Transplant, Bristol, United Kingdom
Amy M. Trottier
Department of Medicine, Division of Hematology, QEII Health
Sciences Centre, Dalhousie University, Halifax, NS, Canada
David Wald
Department of Pathology, Case Western Reserve University,
Cleveland, Ohio, United States
Ambroise Wonkam
Department of Genetic Medicine, McKusick- Nathans
Institute, Johns Hopkins University School of Medicine,
Baltimore, Maryland, United States
Udit Yadav
Division of Hematology, Mayo Clinic, Phoenix, Arizona,
United States
Departments of Pharmacology and Medicine, University of
Toronto, Toronto, ON, Canada
https://t.me/med1917
Foreword
https://t.me/med1917
Across the many therapeutic domains of medicine, one field
stands out as a pioneer in understanding molecular mechanisms of disease and taking this information forward to
deliver highly effective therapies for these conditions.
This field is hematology, and this 5th edition of Molecular
Hematology highlights the substantial progress made in the
field that has defined the molecular basis of many hematological diseases but also developed novel approaches to
therapy that have then gone on to be used as platforms
across a range of other disorders. It is for these reasons that
this book is considered particularly important because it
describes how hematology has become a pathfinder for
molecular medicine in general and has pioneered the application of a range of tools for both disease characterization
and treatment that are now increasingly used across the
whole of medicine.
One obvious question is this: ‘Why has hematology been
so successful and led so many fields of medicine in its ability
to interrogate pathogenesis and develop therapies?’ It has
had the significant advantage of being able to bridge the
clinic and the laboratory, giving it an immediate advantage as
medicine began to shift from bedside subject to one that was
strongly underpinned by the strength of laboratory science.
This has allowed it to move quickly to capitalize on advances
in genetics, cell biology, immunology, and cell therapy moving quickly from laboratory to patients. Another key advantage the field has had is that the cellular framework of clinical
hematology is much more readily accessible than the cells
and tissues in most other organ systems. The obvious
extreme is neuroscience where access to tissue for scientific
evaluation is difficult– if not impossible– and the same is
broadly true about many other organ systems. Hematology
has the benefit that, with a single venipuncture, one accesses
a wide range of different cellular components and even access
to the bone marrow is relatively readily achieved. These must
be crucial reasons why the field has succeeded so quickly.
In disease pathogenesis, hematology has been the first
to utilize many of the molecular tools as cell biology and
genetics to better understand the causation of these disorders. Itwas the characterization of single gene disorders in
conditions such as thalassemia, sickle cell disease, and hemophilia that led the way in terms of our understanding of the
role of individual genetic determinants in mediating a wide
range of these disorders. In some cases, these genetic elements
had been selected for an evolutionary advantage, often due to
pressure from disorders such as malaria but, in any event,
they are classical paradigms for those studying the genetics
of single gene disorders. Similarly, our understanding of
hematologic malignancies led to insights into disease mechanisms responsible for malignant transformation, again
often driven by genetics such as the translocation of Bcr- Abl
that led to the genesis of chronic myeloid leukemia or the
JAK mutations that have underpinned polycythemia rubra
vera. A wide range of these genetic abnormalities have now
been defined in a large number of leukemias and lymphomas, and this has underpinned a much better understanding
of the taxonomy of these diseases such that they are much
better understood mechanistically than diseases are in many
other settings.
A clear understanding of the cellular and molecular basis
of many of these diseases has also led to remarkable success
in developing novel approaches to therapy that have proved
highly effective in many of these disorders. In hematological
malignancies, for example, the initial benefits of chemotherapy for the treatment of ALL set the stage for an era of chemotherapeutic intervention across a wide range of cancers.
Similarly, disorders such as Hodgkin lymphoma were
amongst the first to yield to the effects of modern radiotherapy, again pioneering therapeutic interventions that would
ultimately be used across many diseases. These interventions
gave way to more targeted therapies. Tyrosine kinase inhibitors, in particular, proved enormously successful in treating
diseases like chronic myeloid leukemia, while drugs that
affect growth factors such as ibrutinib have also been successful across a wide range of hematological cancers. Monoclonal
antibodies, as a first form of immune- mediated therapy, have
also had considerable success in treating these disorders. The
anti- CD20 antibody Rituximab ushered in the era of biological therapies and was eventually followed by multiple other
antibody therapies. However, the field has moved on further
xiv Foreword
https://t.me/med1917
to other forms of immune therapy and has been the starting
place for a whole new set of therapeutic modalities using
modified cells such as CAR T cells to treat many disorders.
Another dramatic advance occurring in hematological
disease well before it has been applied in other settings has
been the use of hematopoietic stem and progenitor cells.
Bone marrow transplantation and mobilized blood cell
transplantation have had a wide set of applications in hematology, such that these approaches are now in routine use for
a variety of different conditions, including aplastic anemias
and a range of lymphomas and leukemias where a bone
marrow or mobilized blood cell transplant helps provide the
definitive therapy. In most other therapeutic areas, the role
of hematopoietic stem and progenitor cells is still being
developed, but hematopoietic cell therapy has clearly led the
way in therapeutic terms.
Hematology has also had the benefit of being one of the
therapeutic areas that has begun to benefit from a whole new
type of therapeutic modality, nucleic acidThe ability to manipulate genetic material with antisense
oligonucleotides or with DNA editing technology presages a
whole new revolution in medicine and one where we are
likely to see the benefits first in hematological disorders. The
recent approval of a gene editing- based medicine for beta
thalassemia and sickle cell disease shows how hematology
will continue to lead the way in genetic therapies.
Therefore, it is easy to be persuaded that, across all the
fields of medicine, molecular hematology has been a crucial
pioneering field that set the standards for many others to
follow. The success is also extremely impactful for the
patients who have suffered from these diseases. Many
formsof leukemia are now treatable with very high levels
ofsuccess. Similarly, lymphomas are in many cases curable
with currentinterventions, and we are now seeing the beginnings of a new revolution in genetic therapies that are likely
based therapies.
to contribute to the cures of a range of different genetic
hematological disorders.
The success of molecular hematology in the clinical
setting also reflects the substantial progress in understanding the molecular events that underpin the molecular and
genetic basis of cellular function. The advances in these
domains have been dramatic over the past 40 years, and this
has led to significant insights into fundamental cell biology
as well as cellular pathology. However, there is much
more that we do not completely understand. The role of
additional DNA modification such as epigenetics still needs
to be fully unraveled, while the precise biology that underpins phenomena such as cellular aging, somatic mutation,
and phenomena such as clonal hematopoiesis has yet to be
properly understood. It is clear, however, that many of these
phenomena seen in hematological settings will also continue
to have a major impact across the breadth of medicine.
This volume, therefore, plays a crucial part in our
understanding of the pathology and therapeutic opportunities that underpin hematological disorders. It comprehensively covers all the clinical syndromes and the tools used for
molecular characterization of the diseases and their therapies. It is also a key primer for those trying to understand
disease in other settings. Its broad coverage of many aspects
of molecular hematology all have relevance and importance
to the whole of medicine and insights derived from the
blood have led to very considerable benefits to patients
suffering from multiple diseases around the world. It is no
wonder that Hippocrates chose blood as one of the key
4humors in humans and that it is the only humor that stood
the test of time.
Sir John Bell FRS GBE CH
Regius Professor of Medicine
Oxford University
Preface
https://t.me/med1917
Advances in hematology have been substantial in the four
years since the fourth edition of Molecular Hematology was
published. Gene therapy and gene editing have become
embedded in clinical practice, and implementation of CAR- T
cell technology has resulted in dramatic improvements in
patient outcomes in several hematologic neoplasms. Such
progress in basic science and therapeutics has improved the
diagnosis and care of patients who have a wide range of
hematologic disorders.
Given the great level of innovation, for this edition we
have a new hemato- oncology editor, Professor Hillard M.
Lazarus from the Division of Hematology- Oncology, Case
Western Reserve University, Cleveland, Ohio, USA. Hillard
has overhauled the hemato- oncology chapters of the book,
bringing in many new expert authors covering malignant
hematologic disease.
Around one- third of the book comprises completely new
chapters written by world- renowned experts. Many of the
original authors have continued to support the book, for
which we are immensely grateful, and they have revised and
updated their individual chapters, bringing them fully up- todate with modern practice.
There are also many new illustrations, updated Reading
Lists, and the whole book now reflects contemporary hematology practice.
We firmly believe that a solid understanding of the molecular basis of these disorders aids in diagnosis and treatment
of blood diseases. This volume provides sufficient background information for the practicing clinician and for the
clinical scientists working in this field.
We are proud of this edition, and we owe great thanks to
the Wiley team who have helped us achieve our goal. In
particular, we thank Harini Arumugam, Managing Editor;
Sophie Bradwell, Associate Editor; and Ella Elliott, Editorial
Assistant, as well as all the Wiley team for their patience and
guidance throughout the entire process.
We very much hope you enjoy the fifth edition and, as
always, we welcome any comments or suggestions from
readers, which we will attempt to incorporate into the next
edition.
Drew Provan (a.b.provan@qmul.ac.uk)
Hillard M. Lazarus (hillard.lazarus@case.edu)
https://t.me/med1917
Chapter1
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Beginnings: themolecular
pathology ofhemoglobin
Douglas Higgs and Mohsin Badat
The Laboratory of Gene Regulation MRC Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Headington, Oxford OX3 9DS, UK
Introduction, 1
Normal structure and function of hemoglobin and the globin genes, 2
Molecular pathology of the globin genes, 7
Introduction
The study of hemoglobin and its disorders (hemoglobinopathies) is inextricably linked to the development of molecular
medicine in general. Prominent among these disorders are
the thalassemias. With ~60 000 births of seriously affected
individuals per year, thalassemias are among the most common group of monogenic disorders worldwide. They are
caused by reduced production of the α- and β- globin chains
that form the essential tetrameric oxygen- carrying molecule
hemoglobin (α2β2). The major hemoglobinopathies, α thalas-
semia, β thalassemia, and sickle cell disease, were first recognized as independent clinical entities throughout the last
century. Linus Pauling first used the term “molecular disease” in 1949, after the discovery that the protein structure of
sickle cell hemoglobin differed from that of normal hemoglobin. Indeed, it was this seminal observation that led to the
concept of “molecular medicine,” the description of disease
mechanisms at the molecular level. However, until the development of recombinant DNA technology, starting in the
mid- 1970s, knowledge of genome structure and regulation
was based on microscopy and analysis of the structure and
function of proteins. However, as soon as it became possible
to isolate and study human genes directly, the picture changed
dramatically.
The globin genes provided the first examples of how mammalian genes are regulated. This was mainly because erythroid cells could be easily purified from the peripheral blood
and the earliest erythroid cells released into the circulation
(reticulocytes) contained abundant (>90%) amounts of αand β- globin messenger RNA. Following the discovery of
RNA- dependent reverse transcriptase (by Howard Temin
and David Baltimore), it became possible to radioactively
label DNA transcripts derived from highly enriched globin
RNA isolated from reticulocytes and use this to probe and
The pathophysiology and clinical phenotypes of thalassemia, 12
Conclusion, 16
Further reading, 16
analyze DNA and RNA from normal individuals and those
with the wellvarious hemoglobinopathies. Subsequently, as the ability of
molecular biology to address all aspects of genetics and gene
expression has advanced apace, many of the key insights into
mammalian gene regulation in health and disease have been
first established by studying the globin genes. These advances
include the discovery of mammalian enhancers, promoters,
and insulators; the discovery of splicing in mammals; the
identification of termination of transcription and processing
of RNA by polyadenylation. Importantly, the globin genes
pioneered the idea of regulation of gene expression by longrange enhancers. The globin genes were also used to establish many of the principles by which mammalian mRNA is
translated. By the late 1970s, these new discoveries paved the
way for the application of molecular biology to perform a
prenatal diagnosis to enable genetic counseling and prevent
serious genetic diseases such as the most severe forms of
thalassemia. Today, the most recent attempts to cure genetic
diseases by gene therapy and gene editing are also being
pioneered by the globin field.
By 2003, the first draft of the three billion bases comprising the entire human genome was announced. Together
with exponential increases in the different techniques available to analyze the genome, the epigenome, the transcriptome, and the proteome, it has become possible to examine
in detail virtually any gene in health and disease. Again, the
hemoglobinopathies have first illustrated how coof mutations in the transcriptional, epigenetic, and proteomic landscape can explain the different penetrance of
the hemoglobinopathies in individuals with identical mutations in the globin genes. For example, we now know of
variants in several non- globin genes which can change the
phenotype of a severe hemoglobinopathy into a relatively
mild condition. In summary, understanding how the globin
defined clinical and biochemical features of the
inheritance
Molecular Hematology, Fifth Edition. Edited by Drew Provan and Hillard M. Lazarus.
© 2024 John Wiley & Sons Ltd. Published 2024 by John Wiley & Sons Ltd.
2 Molecular Hematology
31 32 99100
(C)
(A)
β Chains
100
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genes are normally regulated and how this is perturbed in
the hemoglobinopathies provides a sound basis for understanding the principles underlying molecular medicine in
general.
Normal structure andfunction
ofhemoglobin andthe globin genes
The structure andfunction ofhemoglobin
The hemoglobin molecule is a tetramer consisting of two
α- like and two β- like globin chains. The varying oxygen
requirements during embryonic, fetal, and adult life are
reflected in the synthesis of different hemoglobin tetramers
ζ
2ε2
Yolk sac
50
40
30
20
ε
ζ
10
Percentage total globin
0
06
Chromosome 11
ζ
2ε2
Hb Gower 1
Chromosome 16
α
2γ2
Fetal liver
α
β
12
18 24 30 36 1 6 12 18 24 30 36 42 48
Prenatal age (weeks) Birth Postnatal age (weeks)
12345
β-LCR
ζ2γ
2
Hb Portland
Embryo
R1NPRL3 R2 R3
α
2ε2
Hb Gower 2
α
2γ2
Hb F
Fetus Adult
R4
MCS R1-4
α
Bone marrow
γγγε
α
2β2
Hb A
ζ
at each stage of human development (Figure1.1A). However,
they all have the same general structure, consisting of two
different pairs of globin chains, each attached to one heme
molecule (Figure1.1B). Adult and fetal hemoglobins have α
chains combined with β chains (Hb A, α2β2), δ chains (Hb
A2, α2δ2), and γ chains (Hb F, α2γ2). In embryos, α- like chains
called ζ chains combine with γ chains to produce Hb Portland
(ζ2γ2), or with ε chains to make Hb Gower 1 (ζ2ε2), while α
and ε chains form Hb Gower 2 (α2ε2). Fetal hemoglobin is
heterogeneous; there are two varieties of γ chain that differ
only in their amino acid composition at position 136, which
may be occupied by either glycine or alanine; γ chains containing glycine at this position are called Gγ chains, those
with alanine Aγ chains (Figure1.1C).
(B)
2β2
α
2δ2
Hb A
δ
2
α2α
β
1
β
2
α
2
α Chains
(D)
100
90
80
70
60
50
40
30
20
10
Oxyhemoglobin (% Saturation)
Left shift
↓ temperature
↓ 2,3-DPG
+
↓ [H
]
CO
0 10 20 30 40 50
pO
Right shift
(↓ afnity)
↑ temperature
↑ 2,3-DPG
+
]
↑ [H
60 70 80 90
(mmHg)
2
β
1
Iron
Heme
α
1
Figure1.1 (A) Globin production at the α- and β- globin loci during gestation and postnatal life. ζ- and ε- Globin are the first chains to be
expressed during primitive erythropoiesis in the yolk sac, followed soon after by α- and γ- globin at approximately eight weeks’ gestation. β- globin
is expressed at low levels antenatally, but switches with γ- globin at zero to six months postnatally. (B) The hemoglobin tetramer comprised of two
pairs of α- and β- globin chains, each with a prosthetic heme molecule. (C) Schematic of the α- and β- globin chain loci showing the genes and
their cognate enhancers. The genes at the α- globin locus are located downstream of four enhancers (MCS 1- 4), of which MCS- 2 is the most
significant. MCS 1- 3lie within the introns of the gene NPRL3. The β- globin- like genes are similarly located downstream of five regulatory elements
LCR 1- 5. The various hemoglobin products and their globin chain compositions are shown between the loci. (D) The oxygen dissociation curve of
adult hemoglobin with modifying factors.
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