Blood, Vol. 95 No. 1 (January 1), 2000:
pp. 1-6
EDITORIAL
Blood: New designs for a new
millennium
 |
Editorial |
Whether you believe that January 1, 2000, marks the beginning
of the new millennium, this issue of the journal surely represents a
major milestone for Blood and the American Society of
Hematology (ASH). With this issue, we begin self-publishing the
journal, an event we mark by a clean new design. For the past 54 years, commercial publishers, most recently W. B. Saunders Company, ably handled Blood. We sincerely thank the many individuals at
Saunders for their outstanding service over the years, helping to make the journal a premier source for basic and clinical research in hematology. The decision to self-publish was not made out of
dissatisfaction with Saunders or the journal but, rather, reflects the
society's belief that self-publication will offer the editors greater
flexibility in providing the scientific and clinical community with the
best that modern hematology has to offer. With the establishment of an
ASH publishing office, expertly handled by Sabine Beisler and her
staff, and the ongoing exemplary work of the Blood editorial office, headed by Ken Kornfield, we look forward to continuing to
report on innovations in biomedical sciences and clinical care into the
third millennium.
As we embark on these transitions, it is a fitting time to appreciate
the many achievements in the field of hematology, accomplishments that
provide a sense of great optimism for the future. Most agree that the
beginnings of hematology date to the critical technical advances in the
microscope in the 17th century. Red cells were readily apparent in
Leeuwenhoek's improved microscopes, but discovery of the
oxygen-carrying function of hemoglobin awaited the observations of
Hoppe-Seyler in the 19th century. Leukocytes were probably also
apparent to Leeuwenhoek as "colorless corpuscles," but it was not
until the work of Metchnikoff in the late 19th century that their role
in host defense was identified. Due to their smaller size, platelets
were not identified until Addison described "loose or independent
molecules" in the blood in 1842
cells later termed the "dust of
the blood"and it took James Homer Wright to describe their origin
in marrow megakaryocytes in 1906. Thus, by the turn of the last
century, the major blood cell types were described, their origins
identified, and their general functions determined. Wintrobe has
published a poignant essay on the history of early hematology.1 However, little was known of the mechanisms
that account for normal blood production and function and even less known of the basis for their pathologic disorders. The 20th century ushered in a new era in medicine. Today we can often determine the
origin of a patient's hematologic malady at the molecular level and
can occasionally apply rationally designed molecular therapies. The
shift from descriptive physiology and pathology to molecular analyses
of blood and its disorders has been staggering in its rapidity and scope.
Even for nonhematophiles, it is easy to appreciate that our discipline
has made tremendous contributions to the era of molecular medicine,
arguably more than any other specialty within medicine. This editorial
will highlight several of these accomplishments, making the argument
that the continued study of normal and pathologic disorders of the
blood will lead the medical sciences into the future. Clearly, a
molecular understanding of hematologic disease has already provided new
diagnostic, prognostic, and therapeutic strategies and will almost
certainly continue to be translated into major advances in the
medicinal arts of the third millennium.
| |
Hemoglobin |
A comprehensive list of the molecular accomplishments of any
discipline of medicine is beyond the scope of a celebratory editorial, but several developments can be cited as superb examples of how hematology has provided important paradigms for molecular medicine. The
biochemistry of hemoglobin provides a stunning example of how the study
of blood can lead to a thorough understanding of disease and begin to
make inroads into its control. The oxygen-carrying protein hemoglobin
was discovered by Otto Funke in 18512 and its reversible
oxygenation described a few years later by Felix
Hoppe-Seyler.3 Max Perutz determined the crystalline structure of the molecule,4 for which he received the Nobel Prize for Physiology and Medicine in 1957. James Herrick was the first
to report, in 1910, that some patients with severe anemia have
"sickle-shaped" red corpuscles,5 cells previously
recognized in the blood of deer. The abnormal electrophoretic mobility
of hemoglobin S was described in 1949 by Linus Pauling,6
and the characteristic Glu to Val mutation at the sixth position of
S-globin was identified by Vernom Ingram in
1957.7 With the sequencing of normal, sickle, and
thalassemic globin genes, the first human diseases were described at
the nucleotide level. The myriad genetic mutations that can lead to a
single phenotype, such as -thalassemia, have also taught us valuable
lessons on the microheterogeneity of human disease and have provided
the model on which most successful screening strategies for genetic
disease are based.8 Such approaches have already yielded
important dividends: The introduction of prenatal DNA screening has
nearly eliminated new cases of -thalassemia in many
populations.9
Dissection of the -globin gene has yielded other important paradigms
for cell biology and targets for novel therapies of hematologic
disease. Although of little or no clinical consequence when inherited
alone, coinheritance of hereditary persistence of fetal hemoglobin
(HPFH) with homozygous S-globin alleviates the
clinical severity of sickle cell disease. This and other observations fueled intense study of -globin gene expression, a pursuit yielding the first example of a "locus control region," a collection of genetic regulatory elements that affect gene clusters from
afar.10,11 And the desire to pharmacologically mimic HPFH
in patients with sickle cell disease led to our understanding that
cytotoxic agents enhance 
-globin expression,12
ultimately leading to successful clinical trials of hydroxyurea in this
disease.13 Although the precise mechanism by which
hydroxyurea reduces painful vaso-occlusive events in patients with
sickle cell disease may not be entirely dependent on alterations in
-globin gene expression, it is clear that, for the first time,
physicians have available an intervention that can reduce the severity
of the disease.
| |
Hematopoietic growth regulators |
The study of soluble and membrane-bound regulators of hematopoietic
cell growth and differentiation in normal, inflammatory, and malignant
hematopoiesis and their application to clinical medicine has provided
important paradigms in the regulation of cell production, determination
of cell fate, and mechanisms of signal transduction. Translation of
this research to the clinic has also provided a means of stimulating
blood cell production and function for therapeutic benefit.
Carnot was the first to demonstrate that a humoral substance (first
termed hemopoietine) is responsible for the regulation of
erythropoiesis.14 Erythropoietin (Epo) was purified from the urine of patients with aplastic anemia in 1977,15 and
the molecule was cloned in 1985 by scientists at the Genetics
Institute16 and Amgen.17 The cloning and
characterization of hematopoietic growth regulators perhaps best
exemplify the cooperation possible between academic medicine and the
biotechnology industry. In fact, of the 32 recombinant proteins
currently licensed for use in humans in the United States in August
1999, 20 are targeted to hematologic disorders, and 12 affect
hematopoietic cell growth or function (Epo, granulocyte
colony-stimulating factor [G-CSF], granulocyte-macrophage [GM] CSF,
interleukin [IL]-2, IL-11, interferon [IFN]-
, IFN-, IFN-,
and monoclonal antibodies to CD3, IL-2R, tumor necrosis factor
[TNF]- and the TNF-R). The renal source of Epo production was
first appreciated by Jacobson in 1957, and the hormone was first used
in patients with the anemia of renal insufficiency.18 More
recently, Epo therapy has proven valuable in a number of additional
clinical settings.19 In a similar fashion, cytokines that
stimulate neutrophil, monocyte, and megakaryocyte production have been
identified, characterized, cloned, and tested in patients. These
cytokines have also provided important therapeutic advances in patients
with other cytopenias (eg, G-CSF and GM-CSF in
neutropenia20,21 and IL-11 and thrombopoietin (Tpo) in
thrombocytopenia22,23) and in several other clinical
conditions (eg, G-CSF and Tpo in stem cell
mobilization20,24 and M-CSF in infectious
diseases25). Other cytokines that affect marrow-derived
inflammatory cells, such as TNF and IL-6, have also been determined to
play important roles in numerous disease processes. This understanding
has led to additional therapeutic advances. For example,
monocyte-derived TNF- affects neutrophil activation and contributes
to the joint pathology characteristic of rheumatoid arthritis;
neutralizing reagents to this inflammatory mediator have been shown to
ameliorate several refractory clinical disorders.26 The
antiproliferative properties of the IFNs have also been identified and
exploited; the successful therapy of chronic myelogenous leukemia (CML)
or hairy cell leukemia with IFN-27 provides additional
examples of our entry into the age of rational molecular medicine.
Furthermore, the availability of these growth factors and their
receptors has provided important insights into several aspects of
cellular physiology. A number of diseases have been linked to growth
factor or growth factor receptor excess or deficiency (Table
1). Finally, a growing understanding of
the intracellular signaling pathways employed by hematopoietic
cytokines is beginning to provide additional targets for manipulating
blood cell production. Studies of the IFN, hematopoietic cytokine, and
protein tyrosine kinase families of blood cell receptors have given us
JAKs, STATs, and recently, SOCS,37,38 and have expanded the
realm of many previously recognized kinases (PI3K, MAPK, PKC) in
intracellular signaling. A thorough understanding of the elaborate
circuitry that conducts extracellular signals for cell growth,
differentiation, and death will almost certainly provide new targets
for therapeutic intervention. The clinical success of a rationally
designed kinase inhibitor against tumors bearing aberrant
kinases39 is the first example of such signaling therapy.
| |
Cytogenetics and cancer |
For many years, evidence for a genetic role in malignant
transformation was based on studies of animal tumor viruses and
chromosomal changes seen sporadically in rare cancers. That altered
genes cause most or all human cancers was suspected but awaited formal proof. The description of a signature chromosomal change in CML by
Nowell and Hungerford in 1960 (the Ph1
chromosome40) marked a major turning point in our
understanding of the pathogenesis of malignancy. The nature of the
chromosomal change (a precise reciprocal translocation rather than a
deletion) was clarified by Janet Rowley in 1973.41 The fact
that 95% or more of patients with hematopoiesis bear the t(9;22)
translocation (or at least the characteristic fusion gene) established
the primacy of genetic change to a specific form of malignancy, and the
subsequent identification of a cellular homologue (C-ABL) of a
known viral oncogene (v-abl induces pre-B cell lymphoma) at the
site of chromosomal rearrangement (the BCR-ABL fusion gene)
provided the "missing link" between viral oncogenesis and human
cancer biology. The mechanism(s) by which BCR-ABL induces
abnormalities in hematopoietic cell growth is an active area of ongoing
research but is most certainly dependent on the improperly regulated
tyrosine kinase activity of the fusion protein. In the 4 decades since
this sentinel discovery, hematologists and hematopathologists have
continued to provide leading insights in this field. A plethora of new
genes, including those for transcription factors (MYC, SCL/TAL-1,
MLL, AML-1, PLZF, CBF, E2a, RAR), anti-apoptotic factors (BCL-2), cell cycle components (CYCLIND),
growth factors (IL-3), cell surface receptors (TAN-1),
homeobox-containing proteins (HOX 11, PBX-1) and
protein kinases (ABL, LCK) have been identified at the cloned
junction-points of nonrandom chromosomal translocations. One need only
peruse the "Neoplasia" section of Blood to be convinced that the seed planted in 1960 continues to provide a cornucopia for new
genes involved in cell regulation. The pathogenic roles of these and
other newly discovered genes in their corresponding malignancies are
becoming increasingly better understood (Table 2).
Like the studies of t(9;22) and CML, investigation of t(15;17) and
acute promyelocytic leukemia (APL) has provided remarkable insights
into numerous aspects of basic cell biology. However, in this instance,
it was an initial insight from clinicians that provided the vital clue.
As indicated in Table 2, the characteristic chromosomal rearrangement
of APL alters the retinoic acid receptor- gene, fusing it (most
commonly) to the PML gene. However, investigators in China
first demonstrated that a retinoid, all-trans retinoic acid
(ATRA), could induce leukemic cell differentiation in patients with APL
a full 2 years prior to identification of the fusion gene partners in
t(15;17).42 This finding provides an important paradigm:
Some malignancies respond to differentiation therapy. Studies of the
past several years have now provided a molecular explanation for the
clinical result and have yielded surprising new insights into the
control of gene expression through histone acetylation (reviewed in
Redner et al43).
The lessons provided by the genes identified in nonrandom chromosomal
translocations of hematologic malignancies have exerted an enormous
impact on mammalian cell biology. Their identification and
characterization has provided a greater understanding of the proliferation and differentiation of normal cells, has improved our
prognostic ability for patients with leukemias and lymphomas carrying
specific genetic alterations, and has set important precedents for
novel targeted therapies for specific diseases. The use of ATRA in APL
and a kinase inhibitor in CML serve as outstanding examples of how a
better understanding of the genetic alterations in malignancy can be
exploited for therapeutic benefit. The critical role played by the
hematology community in understanding these fundamental genetic
contributions to normal and malignant cell biology should not be underestimated.
| |
Programmed cell death |
Several forms of cell death have been recognized since the
19th century. In addition to necrosis induced by physical agents, some
cells die in a systematic process characterized by nuclear condensation, internucleosomal DNA breakdown, and organized cellular proteolysis. Although initially thought to represent cellular senescence, this form of programmed cell death, termed apoptosis by
Wyllie and Kerr,44 is a developmentally regulated and
reactive process that accounts for the removal of surplus, aged, or
injured cells. Our understanding of the mechanisms responsible for
programmed cell death is growing tremendously, in large measure due to
insights provided by the study of normal and malignant hematopoiesis.
Apoptosis plays a fundamental role in tissue homeostasis, responsible
for the removal of a tadpole's tail and the developmental elimination
of a specific 131 of the 1090 somatic cells of the nematode
Caenorhabditis elegans. As applied to hematology, programmed cell
death is responsible for the purging of autoreactive clones of
lymphocytes,45 reduces the numbers of activated lymphocytes and phagocytes following an inflammatory response,46
accounts for reduced levels of erythropoiesis upon growth factor
withdrawal,47 and is a mechanism by which chemotherapeutic
agents kill malignant cells.48 The description of the
t(14;18) in follicular lymphomas and the cloning of the fusion gene by
several groups in 198549-51 led to the identification of
BCL-2, the fusion partner of the heavy-chain immunoglobulin
locus in these cells. Approximately 80% of follicular and 20% of
diffuse lymphomas bear the signature translocation.52 The
discovery in 1990 that Bcl-2 protein blocks programmed cell death
53 led to the concept that inadequate programmed cell death
contributes to malignancy and provided insights into its molecular
basis. Bcl-2 localizes to the inner mitochondrial membrane, focusing
attention on the role of that organelle and one of its constituent
proteins, cytochrome c, on triggering a cascade of protease mediators
of programmed cell death. Since the initial description of the
BCL-2 gene, a growing family of pro- and anti-apoptotic genes
has been identified based on predicted structure and experimentally
determined function (Bcl-XL, Bcl-XS, Bax, Bad, Bak), opening a
vital new field in cell physiology, regulators of cell death. Although
meaningful clinical manipulation of this system of cell fate remains
for the future, the discovery of BCL-2 and the implications of
apoptosis for normal and malignant cellular development are enormous.
| |
Integrins |
Cell-matrix and cell-cell interactions provide the adhesion
necessary for maintenance of proper tissue architecture. Moreover, in
addition to soluble mediators of cell signaling, direct cell-cell contact is also a critical mode of intercellular communication. Among
the many cellular adhesion systems that have been studied, blood cell
interactions with the endothelium and other blood cells have provided
valuable and unique insights into the biology of inflammation and stem
cell trafficking. The study of platelet-platelet interactions, however,
holds a special place in integrin biology; this field can boast the
first example of the successful manipulation of cell adhesion for
therapeutic benefit.
In 1918 Edward Glanzmann reported on patients who displayed excessive
mucocutaneous bleeding but had normal platelet counts. Although
Glanzmann was likely studying multiple functional platelet disorders,
subsequent investigations using allogeneic antiplatelet antibodies54 and platelet membrane biochemistry revealed
that the bleeding diathesis bearing his name is due to defective
platelet fibrinogen binding. The predominant platelet fibrinogen
receptor was identified as glycoprotein IIb/IIIa (now termed integrin
IIb/3 by aficionados) and is a member of
the growing family of heterodimeric molecules known as integrins, vital
for cell-cell and cell-matrix interactions. The binding between
IIb/3 and fibrinogen is probably the
best-studied interaction between an integrin and its ligand, and its
failure in Glanzmann's thrombasthenia serves as the founding member of
diseases of intercellular interaction. The critical binding site,
defined by the Arg-Gly-Asp tripeptide on fibrinogen, is responsible for
both intermolecular adhesion and for propagating platelet thrombi.
Ischemic cardiovascular disease is the most common cause of death in
the Western world and, unfortunately (due in large measure to the
export of high-fat, fast-food diets and cigarettes), is quickly
spreading through the developing world. Although multiple factors
conspire to generate the ulcerating atherosclerotic plaque, it is the
hemostatic system that initiates the final thrombotic event. Occlusive
thrombus formation begins with the adhesion of blood platelets to
extracellular molecules present in the plaque, including collagen, von
Willebrand factor, and tissue factor-generated fibrin. It is unusual
for this initial layer of platelets to occlude the vascular lumen;
rather, platelet adhesion begets platelet activation, which in turn
results in IIb/3- and fibrinogen-mediated platelet aggregation. This latter event provides a fait accompli. Studies designed to understand the molecular basis for this series of
events have been extremely fruitful. Engagement of any number of
platelet receptors (collagen, adenosine diphosphate, fibrinogen, von
Willebrand factor) results in activation of multiple intracellular signaling pathways. Much has been learned of the kinases and second messengers responsible for this process.55 Ultimately,
effector molecules are recruited to the cytoplasmic domains of other
integrins (including
IIb/3;56), altering their
extracellular conformation and yielding a high-affinity ligand binding
site. Unfortunately, not all of the details of such outside-in and
inside-out signaling are presently in place. Nevertheless, it is clear
that blockade of integrin function, particularly that responsible for
platelet aggregation, should do much to alleviate thrombotic vascular
disease and has been an important goal in vascular biology. Two
molecular approaches to this problem have recently yielded major dividends.
Using a neutralizing murine monoclonal antibody to human
IIb/3, Coller and colleagues showed that
platelet adhesion and aggregation could be reduced both in vitro and in
vivo.57,58 Clinical trials of a humanized fragment of this
reagent have shown it reduces the incidence of restenosis following
coronary angioplasty.59 In addition, using an understanding
of the binding properties of fibrinogen and
IIb/3, several small-molecule reagents
have been developed to interfere with this aspect of platelet function. These agents have also been clinically tested and found to reduce thrombotic events in a number of pathologic settings.60 The rational use of our understanding of platelet integrin function provides the first example of novel molecular approaches to cell adhesion therapy. Based on this paradigm, intervention in other cell-cell interactions could play an important role in preventing the
metastatic spread of cancer by interfering with tumor angiogenesis (eg,
blockade of integrin V3);
ischemia-reperfusion injuries in shock, stroke, or myocardial
infarction (eg, blockade of 2 integrins); or the
pathologic airway changes induced by inflammatory cell infiltration in
asthma (eg, inhibition of 4/1 integrin). Clinical trials of anti-integrin reagents are already under way in each
of these settings. Once again, hematology has provided the critical
precedents in a field that stretches across essentially all disciplines
of medicine.
| |
Blood coagulation |
Hemophilia, perhaps more than any other hematologic disorder,
decorates the history of Western culture. The disease was almost certainly recognized in the second century AD: The Talmud describes the
decision of Rabbi Judah to withhold circumcision from the son of a
woman who had 3 previous sons bleed to death following the
procedure.61 However, Queen Victoria of England began the most colorful chapter of hematology in Western history.62
An obligate carrier of hemophilia A, Queen Victoria ultimately passed the disease to about 20 people, including the only son of Nicholas and
Alexandra (Victoria's granddaughter) of Russia. It has been argued
that the Bolshevik Revolution in 1917 in Russia might never have taken
place if not for the preoccupation of the czar and his family with
their ailing son, Alexis.1
John Conrad Otto established the genetics of hemophilia in 1803, but
the biochemistry was not worked out until the 1950s, when hemophilia A
and B were distinguished based on complementation of coagulation tests
from different families.63 Although the discovery of
cryoprecipitate in the 1960s by Judith Poole led to the first major
therapeutic advances for hemophilia A, the purification and cloning of
coagulation factors VIII and IX in the 1980s provided purified and now
recombinant products for specific therapy and led to characterization
of the mutations that cause the human disorders. These studies have
given us new examples of disease-causing mutations such as an
intron-based genetic inversion.64 Equally heroic plasma
purifications led to the cloning and characterization of the
coagulation factors, naturally occurring anticoagulant and fibrinolytic
factors involved in normal and pathologic hemostasis. These efforts
have provided important new clinical insights; mutations of several
clotting and anticoagulant proteins lead to hypercoagulable states,65 and the use of fibrinolytic agents in patients
with acute coronary and cerebral thrombosis has improved
survival.66 The study of coagulation factor biosynthesis
has also provided important new insights into the processing necessary
for protein secretion; evaluation of patients with combined factor V
and VIII deficiency has revealed a chaperone-type molecule necessary
for secretion of the 2 structurally related proteins.67,68
Detailed study of the structure-function relationships of the
coagulation proteins has led to a better understanding of the kinetics
of multienzyme complexes,69 and hemophilia B has provided
medicine with one of the few examples of successful gene therapy in
large animal models of human disease.70,71
From the foregoing examples, it is clear that our molecular
understanding of hematologic disorders grows daily and that its clinical rewards are improved diagnostic, prognostic, and therapeutic approaches to patient care. Although these are examples of how the
study of blood and its disorders on a molecular level has advanced both
basic science and clinical medicine, an equally impressive list of
advances can be compiled for work in cell biology. Elucidation of the
ABO and Rh erythrocyte antigenic systems allows virtually unfettered
red cell transfusion therapyyielding revolutions in surgery, the
treatment of trauma, and the care of patients with chronic anemias.
Advances in chemotherapy, stem cell biology, transplantation, and
immunology are only part of the long list of accomplishments based on
hematologic investigation begun in the second millennium and that will
undoubtedly expand greatly in the third. The editorial board of
Blood looks forward to our role of reporting, highlighting, and
celebrating these accomplishments in the basic and clinical aspects of
hematology.
Kenneth Kaushansky, MD
Editor-in-Chief
Seattle, WA
| |
Acknowledgments |
I wish to thank Drs George Stamatoyannoupolos, Michael Cleary,
John Harlan, Evan Sadler, Virginia Broudy, and Jan Abkowitz for their
very helpful suggestions. I would also like to acknowledge the
countless investigators not cited here for reasons of limited space.
Indeed, anyone who has reported the results of basic or clinical
hematologic research has contributed to the success story that is
modern hematology.
| |
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