Page 1064 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 60 Myelodysplastic Syndromes 947

that the increased incidence in men overall is likely caused by differ- or more hematopoietic compartments; this may or may not coincide
ences in occupational exposures, but this has never been clearly with genetic lesions that lead to ineffective hematopoiesis and cyto-
demonstrated. Indeed, the only toxic chemical exposure definitively penias, at which point MDS also becomes clinically evident. 56
43
proven to cause MDS is benzene, which is now significantly less Proving that MDS is a clonal disease was not as straightforward
prevalent in industrial workplaces than it had been in the past. Other a proposition as it was for AML, in which examination of the bone
environmental exposures, including cigarette smoking, have been marrow typically identifies sheets of abnormal, morphologically
postulated but never definitively proven to predispose to MDS. 44 identical blasts. In contrast, for MDS—particularly low-risk disease
MDS in the United States and Western Europe is epidemiologi- in which blasts are rare and the marrow architecture is disorganized
cally similar, but there are differences between these geographic and heterogeneous—a clonal origin was not immediately obvious
45
46
regions and other parts of the world. In Asia and Eastern Europe, based on morphology alone. Nonetheless, the clonal nature of MDS
for instance, the average age at MDS diagnosis is younger, and the was established in the 1980s by studies that showed skewed inactiva-
frequency of both severe cytopenias and risk of progression to leuke- tion of glucose-6-phosphate dehydrogenase (G6PD), an X-linked
47
mia may differ. Some of these differences are likely caused by gene, in the hematopoietic cells of female MDS patients heterozygous
57
variance in environmental exposures. In Japan, for example, broad for G6PD deficiency. More recent studies have used deep sequenc-
population-wide exposure to ionizing radiation from the atomic ing techniques to track the clonal evolution from MDS into AML
bombings of Hiroshima and Nagasaki in the 1940s continued to and have confirmed that in these cases, the preexisting MDS is as
48
influence MDS incidence well into the 1990s. However, the cause highly clonal as the resulting secondary AML. 58
of differences in MDS subtypes, such as the low incidence of RARS That MDS is a disorder of stem or early progenitor cells has been
59
in Japan compared with the West, remain unclear. more difficult to prove. Some of this difficulty is a reflection of the
Indeed, the two exposures most consistently associated with elusiveness of human HSCs themselves: the ability of different human
subsequent development of MDS are ionizing radiation and cytotoxic cell populations to self-propagate after xenotransplantation into
chemotherapy, and MDS arising in these settings, known as therapy- immunodeficient mice, considered the functional hallmark of “stem-
related MDS or t-MDS, is frequently characterized by TP53 muta- ness,” varies with the exact degree of immunodeficiency of the mice
60
49
tions, multiple large-scale chromosomal abnormalities including into which the cells are transplanted. Moreover, xenotransplant
complex karyotypes (most commonly defined as ≥3 clonal chromo- experiments using immunophenotypically defined hematopoietic
−
+
−
50
somal anomalies), and frequent transformation to treatment- stem and progenitor cells (HSPCs; classically CD34 CD38 Lin )
51
refractory AML. In the United States, radiation is most frequently from MDS patients have not shown a striking proliferative or self-
61
encountered as treatment for other cancers, and radiation fields that renewal advantage for the MDS cells compared to normal controls,
include the hips or pelvis, the most active sites of hematopoiesis in and the degree to which these experiments accurately depict the
52
adults, probably pose the greatest risk. Less commonly, exposure to clonal dynamics of MDS in humans is unclear. Some have further
radiation can occur as the result of occupational exposures (e.g., been troubled by the observation that lymphoid clonal expansion,
workers at nuclear reactors) or industrial accidents. Among chemo- which should occur with near-equal frequency to myeloid clonal
therapeutic agents, there is a substantial difference in the risk of expansion if MDS is indeed a disorder of very early hematopoietic
subsequent MDS. In particular, alkylating agents (e.g., cyclophospha- progenitors, is only rarely observed. 62,63 However, more recent studies
53
mide and melphalan) appear to carry the greatest risk, while the risk combining immunophenotypic analysis with deep sequencing of
with nucleoside analogues is lower. Of particular note, the rapidly clonal mutations in MDS cells have shown that the mutations appear
progressive AML seen in association with topoisomerase inhibitors to originate exclusively in the most primitive, stem-cell-like compart-
64
(e.g., doxorubicin, etoposide) is not typically preceded by MDS. 54 ment, and others have shown that differential expansion of specific
progenitor compartments may vary between different phenotypes
65
and risk profiles of MDS. This evidence has contributed to the
PATHOBIOLOGY conclusion that MDS is, in fact, a disorder of transformed HSCs. 66
The conceptualization of MDS as a stem cell disorder explains,
The past 10 years have witnessed significant advances in our under- in large part, why it is so refractory to most attempts at conventional
standing of the rich and complex pathobiology underlying MDSs. therapy. Both normal HSCs and leukemia stem cells remain quiescent
MDS is now recognized to arise from interactions between acquired for much of their lifetimes, and during these periods they are largely
genetic mutations in hematopoietic precursor cells, alterations in the impervious to any agents, such as most chemotherapeutic drugs, that
67
microenvironment of the bone marrow, and dysregulated immune exert their effects during active DNA replication. Overcoming the
surveillance. Broadly speaking, the acquisition of sequential muta- intrinsic resistance to therapy conferred by the existence of quiescent
tions in precursor cells drives the development of a malignant clone, reservoirs of disease is one of the central challenges in developing
and alterations in the microenvironment and the immune response effective treatments for MDS. 68
allow that clone’s expansion. This section details our current under-
standing of these concepts.
Genetic Alterations
Myelodysplastic Syndrome Stem Cells Like other cancers, the core hypothesis underlying MDS pathogenesis
is that the originating clone of MDS becomes increasingly abnormal,
One of the central challenges in understanding the pathogenesis of and ultimately malignant, through the sequential accumulation of
69
MDS has been isolating the cell of origin and understanding that acquired genetic or epigenetic abnormalities. Improvement in our
cell’s mechanisms of self-renewal and propagation, both of which are understanding of how these abnormalities are acquired, how they
55
necessary for the establishment of a malignant clone. In theory, the interact with each other, and their impact on pathways affecting
exact state of hematopoietic differentiation from which a malignant proliferation, self-renewal, and differentiation, has been one of the
clone arises could vary between cases of MDS, but the capacity for major advancements in the study of MDS over the last decade.
self-renewal implies that the origin cell was either a hematopoietic Several different classes of genetic abnormalities may be found in
stem cell (HSC), and thus possessed intrinsic self-renewal capabilities, MDS. The first to be recognized were cytogenetic abnormalities on
71
70
or it was a more differentiated myeloid progenitor that acquired the standard karyotyping, which are present in about 50% of patients.
ability to self-renew. Clonal expansion then occurs through the A second category of cryptic chromosomal aberrations, including
acquisition of new mutations or epigenetic alterations that either microdeletions and copy number-neutral loss of heterozygosity, are
enhance proliferation or confer resistance to apoptosis. MDS presum- too small to be detected by karyotype but may be found with fluo-
72
ably becomes morphologically apparent when the dominant clone rescence in-situ hybridization (FISH) or single nucleotide polymor-
73
acquires a subsequent genetic lesion that leads to dysplasia within one phism (SNP) arrays. The most common type of abnormality,