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Perspective
Ribosomes and marrow failure: coincidental association or molecular paradigm?
Johnson M. Liu and Steven R. Ellis
Gene products mutated in the inherited
bone marrow failure syndromes dyskeratosis congenita (DC), cartilage-hair hypoplasia (CHH), Diamond-Blackfan anemia
(DBA), and Shwachman-Diamond syndrome (SDS) are all predicted to be involved in different aspects of ribosome
synthesis. At this moment, however, it is
unclear whether this link indicates a
causal relationship. Although defective
ribosome synthesis may contribute to
each of these bone marrow failure syndromes (and perhaps others), precisely
which feature of each disease is a consequence of failure to produce adequate
amounts of ribosomes is obscured by the
tendency of each gene product to have
extraribosomal functions. Delineation of
the precise role of each gene product in
ribosomal biogenesis and in hematopoietic development may have both therapeutic and prognostic importance and perhaps even direct the search for new bone
marrow failure genes. (Blood. 2006;107:
4583-4588)
© 2006 by The American Society of Hematology
Introduction
Inherited bone marrow failure syndromes including dyskeratosis
congenita (DC), cartilage-hair hypoplasia (CHH), DiamondBlackfan anemia (DBA), and Shwachman-Diamond syndrome
(SDS) have long fascinated and challenged geneticists and hematologists. This heterogeneous group of disorders is characterized by
bone marrow failure and the variable presence of congenital
anomalies and cancer predisposition (Table 1). While there has
been rapid progress in identifying gene defects in nearly all the
disorders, understanding the molecular pathophysiology has
lagged behind in most instances. Intriguingly, genes mutated in
many of these disorders encode factors involved in ribosome
synthesis, suggesting a link between this fundamental cellular
process and marrow failure. In this “Perspective,” we wish to
define this association and critically assess its validity in the light of
new research.
Broadly speaking, the genes mutated in the inherited marrow
failure syndromes (reviewed in J. M. Lipton, J.M.L., and A.
Vlachos, manuscript submitted) have widely disparate functions
(Fanconi anemia genes, c-MPL, GFI1, ELA2, RUNX1, HOXA11,
GATA1, and others) without an obvious molecular interrelationship. By contrast, genes mutated in X-linked DC,1 CHH,2 DBA,3
and SDS4 are all predicted to be involved in aspects of ribosome
synthesis. Complicating this picture, however, is the fact that some
of the factors encoded by these genes are multifunctional, influencing one or more critical cellular processes in addition to ribosome
synthesis. The most extensively studied bone marrow failure
syndrome from this perspective is X-linked DC, which is caused by
mutations in DKC1 (its encoded protein also known as dyskerin).1
Dyskerin is a putative pseudouridyl synthase found in so-called
H/ACA ribonucleoprotein complexes involved in ribosomal RNA
(rRNA) modification. Since its discovery, dyskerin has also been
shown to be a component of other ribonucleoprotein complexes
including telomerase.5 A similarly complex picture is emerging for
CHH. The gene affected in CHH is RMRP, which encodes the RNA
component of ribonuclease mitochondrial RNA processing (RNase
MRP).2 RNase MRP is a multifunctional ribonucleoprotein complex involved in cleaving rRNA precursors, processing of RNA
primers used in mitochondrial DNA replication, and the turnover of
certain cell cycle–regulated mRNAs. The only gene linked to DBA
to date encodes ribosomal protein S19 (RPS19),3 which in yeast is
required for the maturation of 40S ribosomal subunits.6 Here again,
the human RPS19 protein has been proposed to have a function
outside of this role.7 Finally, several studies have suggested that
SBDS, mutations in which cause SDS,4 encodes a protein involved
in ribosome synthesis.8,9 Thus, although defective ribosome synthesis may contribute to each of the bone marrow failure syndromes
under discussion here, precisely which feature, if any, of each
disease is a consequence of failure to produce adequate amounts of
ribosomes is obscured by the tendency of each gene product to
have extraribosomal functions (Figure 1).
From the Feinstein Institute for Medical Research, Manhasset, NY; Schneider
Children’s Hospital, New Hyde Park, NY; and the Department of Biochemistry
and Molecular Biology, University of Louisville School of Medicine, KY.
Reprints: Johnson M. Liu, Head, Les Nelkin Memorial Pediatric Oncology
Laboratory, Schneider Children’s Hospital, Pediatric Hematology/Oncology &
Stem Cell Transplantation, New Hyde Park, NY 11040; e-mail: [email protected].
Submitted December 6, 2005; accepted February 9, 2006. Prepublished online as
Blood First Edition Paper, February 28, 2006; DOI 10.1182/blood-2005-12-4831.
© 2006 by The American Society of Hematology
BLOOD, 15 JUNE 2006 䡠 VOLUME 107, NUMBER 12
Ribosome synthesis
The human ribosome is composed of 4 ribosomal RNAs and a
minimum of 80 different ribosomal proteins. In addition to these
structural components of the ribosome, there are well over 100
additional factors involved in its biosynthesis.10 These factors
include components of the RNA polymerase I transcriptional
machinery, small nucleolar ribonucleoprotein complexes involved
in rRNA modification, a host of RNA helicases and other chaperonelike factors, nucleases, factors involved in nucleolar-cytoplasmic
transport, and structural components of the nucleolus. In yeast, the
genes encoding the majority of these factors are essential or cause
significant growth defects when mutated, indicating that they play a
critical role in cell growth and division. Collectively, these genes
represent hundreds of potential target loci that when mutated may
contribute to human disease, making it imperative that we understand the pathophysiology underlying the handful of human
disorders currently linked to factors involved in ribosome synthesis.
4583
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4584
BLOOD, 15 JUNE 2006 䡠 VOLUME 107, NUMBER 12
LIU and ELLIS
Table 1. Genetic disorders linked to molecular defects in ribosomal biogenesis
Disease
Gene defect
Clinical features
X-linked dyskeratosis congenita
DKC1
Abnormal skin pigmentation, nail dystrophy, bone marrow failure, cancer, others
Cartilage-hair hypoplasia
RMRP
Skeletal defects and short stature, hypoplastic anemia, lymphoma, others
Diamond-Blackfan anemia
RPS19
Bone marrow failure, craniofacial abnormalities, cancer, others
Shwachman-Diamond syndrome
SBDS
Bone marrow failure, pancreatic insufficiency, short stature, leukemia, others
Treacher Collins syndrome
TCOF1
Craniofacial abnormalities
Of this group, only Treacher Collins syndrome is not associated with bone marrow failure.
Many of the structural components of the ribosome, as well
as additional biosynthetic factors, have been shown to possess
extraribosomal functions, ranging from roles in replication and
DNA repair to serving as receptors on the cell surface.11 More
recently, an emerging body of data has linked specific ribosomal
proteins to active roles in cellular stress response,12,13 proliferation,14 and apoptosis.15 The challenge in studying these factors
and their roles in human disease is sorting out their more general
roles in modulating protein synthetic capacity from functions
more specific to a given factor, a challenge further complicated
by the diverse and variable array of clinical phenotypes
observed in the bone marrow failure syndromes discussed. Here
we summarize some of the current approaches being used to
mechanistically dissect these disorders and suggest possible
venues for future research.
DKC1 and X-linked DC: importance of
additional disease-linked genes
We begin our analysis with X-linked DC, which may serve as a
model wherein ribosomal dysfunction plays a role in bone marrow
failure but is clearly not the sole explanation. Ectodermal dysplasia
and hematopoietic failure characterize DC (reviewed in Liu and
Dokal16). In addition to the classic triad of abnormal skin pigmentation, dystrophic nails, and leukoplakia of mucous membranes, there
are a number of other somatic abnormalities.17 The most common
of these are epiphora, developmental delay, pulmonary disease,
short stature, esophageal webs, dental caries, tooth loss, premature
Figure 1. Schematic relationship between ribosome synthesis and SDS, DBA,
TCS, CHH, AD, and DC. TCS is depicted by dotted lines, as it does not cause bone
marrow failure. Putative functions in ribosomal biogenesis attributed to each gene
product include 40S ribosomal subunit maturation, RNA polymerase I (pol I)
transcription, rRNA methylation, rRNA cleavage, and pseudouridylation (pseudo-U)
of rRNA. Illustration by Frank Forney.
gray hair, and hair loss. Pancytopenia is the hematologic hallmark
of DC, and approximately 50% of patients develop severe aplastic
anemia and greater than 90% of individuals at least a single
cytopenia by 40 years of age.
Dyskeratosis congenita is most commonly inherited as an
X-linked recessive disorder, although autosomal dominant (ADODC) and autosomal recessive (AR-DC) forms exist. The gene
responsible for the X-linked form was subsequently identified as
DKC1.1 DKC1 encodes dyskerin, a nucleolar protein that is 1 of 4
proteins associated with small nucleolar ribonucleoprotein particles (snoRNPs) involved in rRNA maturation. Dyskerin associates with the H/ACA (referring to characteristic short snoRNA
sequences) class of snoRNPs, which function in the pseudouridylation of rRNAs. Structural similarities between dyskerin and yeast
and bacterial pseudouridine synthases suggested that dyskerin
might be the active human pseudouridine synthase in the H/ACA
complexes. At the time of its discovery, this was the only known
function of dyskerin, thus leading to the inference that defects in
ribosome synthesis, resulting from failure to properly modify
rRNA, are responsible for the manifestations of X-linked DC
(Figure 2).
Soon thereafter, however, it became clear that dyskerin had
other functions within cells. Most importantly, dyskerin was found
to be associated with the telomerase complex.5 The telomerase
ribonucleoprotein complex, which is at times nucleolar, includes
the telomerase reverse transcriptase TERT and the telomerase RNA
component TERC, which acts as a template for the synthesis of the
TTAGGG telomere repeats at the ends of chromosomes. Telomeres
Figure 2. Putative biochemical function for DKC1, TCOF1, SBDS, RPS19, and
RMRP in ribosomal biogenesis. For simplicity, the mammalian rRNA processing
pathway is depicted, whereas the putative function of each gene product is deduced
from data obtained from yeast and human orthologs. In the mammalian rRNA
processing pathway, cleavages at the external transcribed sequence (5⬘ETS) and
internal transcribed sequences (ITS1 and ITS2) lead to maturation of 18S, 5.8S, and
28S rRNA species. The 18S rRNA is a component of the 40S ribosomal subunit. The
5.8S and 28S rRNAs, together with the 5S rRNA (not shown), are components of the
60S ribosomal subunit. The 40S and 60S subunits are assembled into 80S
ribosomes. Illustration by Frank Forney.
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BLOOD, 15 JUNE 2006 䡠 VOLUME 107, NUMBER 12
protect the ends of chromosomes from degradation and aberrant
fusion events. TERC has an H/ACA-like domain and is associated
with dyskerin, GAR1, NOP10, and NHP2. Here, dyskerin appears
to serve as a structural component of the telomerase complex in
contrast to its proposed role in the rRNA-modifying snoRNPs, as
telomerase has no pseudouridylation target. With the discovery that
cells from patients with X-linked DC and ADO-DC exhibit
shortened telomeres18 and the subsequent identification of causative mutations in TERC in ADO-DC,19 it was presumed that
defective telomerase activity, rather than impaired ribosomal
maturation, underlies the bone marrow failure seen in DC. Mutations in the TERT reverse transcriptase gene have also been
identified in aplastic anemia patients with short telomeres, further
implicating the telomerase pathway.20
Although the pendulum has swung away from ribosome
synthesis and toward telomere maintenance as explaining DC
pathophysiology, the observation that the X-linked form of the
disease is more severe than the autosomal dominant form leaves
open the possibility that an effect on ribosome synthesis may
contribute to phenotypic outcome. An extremely severe variant of
DC known as Hoyeraal-Hreidarsson syndrome, which leads to
aplastic anemia, immunodeficiency, and cerebellar hypoplasia, is
also caused by mutations in DKC1, demonstrating that allelic
differences in the same protein could lead to more severe phenotypes.21 We are also left with the puzzling features of the dyskerin
hypomorphic mouse model,22 which displays some of the clinical
features of DC prior to the onset of significant telomere shortening.
That these mice display defects in ribosome synthesis suggests
there may be some overlap in phenotype associated with defects in
ribosome synthesis and telomere maintenance. In addition, 2
dyskerin patient mutations introduced into murine embryonic stem
cells caused defective pseudouridylation and decreased pre-rRNA
processing, but only 1 of the 2 mutations affected telomerase
activity.23 Thus, in yeast,24 Drosophila,25 and 2 different mouse
models defects in dyskerin orthologs lead to a reduced rate of
production of mature rRNAs and accumulation of unprocessed
precursor molecules. Collectively, these data argue for involvement
of both ribosome deficiency and telomerase dysfunction in DC
pathophysiology, with the contribution of each possibly dependent
on the particular mutation site within dyskerin. The crystal
structure of the dyskerin-NOP10-GAR1 complex has recently been
deduced,26 identifying a dyskerin domain within which most DC
mutations cluster. Current efforts employing detailed genotype/
phenotype correlations may assist in clarifying the relative contributions of ribosome synthesis and telomere maintenance to the
clinical features of DC.
RMRP and cartilage-hair hypoplasia:
genotype/phenotype relationships
CHH, also known as metaphyseal chondrodysplasia McKusick
type, was first described by McKusick et al27 as a form of dwarfism
in the Amish. CHH is an autosomal recessive disorder characterized by cartilage/skeletal defects with short stature, fine sparse
blond hair, and hypoplastic anemia. The anemia, while typically
mild, can be persistent and severe as in DBA.28 CHH is also
associated with defective cellular immunity,29 gastrointestinal
dysfunction,30 and a predisposition to cancer (primarily lymphoma).31 Mutations in the untranslated RMRP gene were found
to cause CHH, with an ancient founder mutation in Finland.2
RIBOSOMES AND MARROW FAILURE
4585
RMRP encodes the RNA component of the RNase MRP
complex and is classified as a small nucleolar RNA (RMRP and the
previously mentioned TERC are the 2 only known nonmitochondrial examples of RNA genes that when mutated lead to disease). In
yeast, the RMRP ortholog NME1 (nuclear mitochondrial endonuclease-1) has multiple functions and is essential for viability.32 First, it
functions in mitochondrial DNA replication by cleaving RNA
primers associated with nascent organelle DNA.33 Second, some
nme1 mutants exhibit a late mitotic cell cycle arrest associated with
increased cyclin B2 mRNA levels (normally, the RNase MRP
complex cleaves the 5⬘ untranslated region of cyclin B2 mRNA).34
Third, RNase MRP plays a role in ribosomal RNA processing.35 In
both yeast and humans, RNase MRP cleaves pre-rRNA within
internal transcribed sequence 1 (ITS1), influencing the maturation
of the 5⬘ end of 5.8S rRNA (Figure 2). Consistent with this latter
function, RNase MRP is mainly located in the nucleoli packaged as
one of the snoRNPs. In humans, the RNase MRP complex consists
of the RNA component and at least 10 protein subunits,36 of which
8 are shared with ribonuclease P, involved in tRNA precursor
maturation.
Recent work has suggested that it is the function of RMRP in
cell cycle–regulated mRNA turnover that underlies the bone
marrow failure seen in CHH.37 This conclusion is supported by the
discovery of novel RMRP mutations that lead to another autosomal
recessive growth disorder known as anauxetic dysplasia (AD),
which is characterized by extreme short stature, hypodontia, and
mild mental retardation. While the growth abnormalities in anauxetic dysplasia are reminiscent of those in CHH, hypoproliferative
bone marrow dysfunction and cancer susceptibility are seen only in
CHH and not in anauxetic dysplasia. In vitro studies have shown
that human fibroblasts overexpressing the CHH founder mutation
⫹70A ⬎ G exhibited both impaired rRNA endonucleolytic cleavage and cyclin B2 mRNA cleavage (and hence increased cyclin B2
mRNA levels), whereas cells overexpressing anauxetic dysplasia
mutations exhibited only rRNA cleavage abnormalities.37 These
genotype/phenotype studies imply that while RMRP mutations can
disrupt 5.8S rRNA maturation (and hence 60S ribosomal assembly)
resulting in some of the clinical features of CHH, it is likely the
concurrent disruption of cyclin B2 mRNA degradation and mitotic
delay that explains the bone marrow failure phenotype in CHH
(Figure 1).
RPS19 and DBA: focus remains on ribosomes
We now turn our focus to DBA, currently the only known human
disease caused by defects in a structural component of the
ribosome, namely RPS19. DBA is a pure red cell aplasia predominantly seen in infancy and childhood. In addition to anemia, other
significant cytopenias have been reported.38,39 An elevated erythrocyte adenosine deaminase activity (found in approximately 85% of
patients), macrocytosis, and an elevated fetal hemoglobin level are
supportive but not diagnostic of DBA. Congenital anomalies
including thumb malformations and various others are seen in 50%
of DBA patients and, in turn, half of these are craniofacial
abnormalities.40
Approximately 45% of DBA cases are familial.41 The first DBA
gene, mutated in about 25% of patients, was cloned and identified
as RPS19, which encodes a protein component of the 40S
ribosomal subunit.3,42 Patients are generally heterozygous with
respect to RPS19 mutations, indicating that the disease likely
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4586
LIU and ELLIS
results from protein haploinsufficiency.43 Studies of the yeast
ortholog of RPS19 indicate it is required for the maturation of 40S
ribosomal subunits6 (Figure 2). Yeast cells deficient in RPS19 have
a reduction in the steady-state level of 40S ribosomal subunits and
compromised protein synthetic capacity. Pre-40S particles that
accumulate in cells depleted of RPS19 are retained in the nucleolus
and fail to recruit factors needed for rRNA processing and transport
to the cytoplasm.
If human RPS19, like its yeast ortholog, is required for the
maturation of 40S ribosomal subunits, questions remain as to
how haploinsufficiency for an essential ribosomal protein
results in the predominantly hematopoietic manifestations of the
disease. Ellis and Massey44 have proposed that differences in the
level of individual ribosomal components can make proteins
limiting for ribosome assembly in some tissues and not others,
when present in a haploinsufficient state. As discussed later, in
the section on Treacher Collins syndrome, this may explain the
tissue specificity characterizing disorders such as DBA. Recent
studies by other investigators showing that RPS19 interacts with
the oncoprotein Pim1 have raised an alternative hypothesis, in
which RPS19 links signal transduction pathways with the
translational machinery.45 Finally, the observation that crosslinked dimers of RPS19 function as agonists and antagonists of
the C5a complement receptors7 suggests other extraribosomal
functions for RPS19 that may contribute to DBA pathophysiology in a manner not currently understood.
As the different functions for RPS19 are gradually clarified,
ongoing efforts to genotype DBA patients and correlate clinical
phenotypes with RPS19 mutations may assist in distinguishing
between these alternative hypotheses. Likewise, identifying other
genes responsible for DBA other than RPS19 will be critical in
directing further research, as well as in either validation or
questioning of the ribosome and marrow failure link.
SBDS and Shwachman-Diamond syndrome:
new player on the block
Shwachman-Diamond syndrome (SDS), first described in 1964, is
an autosomal recessive disorder characterized by neutropenia,
exocrine pancreatic insufficiency, and metaphyseal dysostosis.46,47
Neutropenia, found in 88% to 100% of patients, is the hematologic
hallmark of SDS, and in some patients there is also a defect in
neutrophil chemotaxis (reviewed in Dror and Freedman48). Pancytopenia occurs in 10% to 65% of cases and may precede progressive bone marrow dysfunction characterized by severe aplastic
anemia, myelodysplastic syndrome, or acute leukemia, usually of
myeloid origin.49
Most cases of SDS are caused by mutations in the SBDS
gene.4 While SBDS is highly conserved in species as divergent
as archaebacteria, little is known regarding the precise function
of its gene product. The localization of the archaeal SBDS in an
operon with subunits of the exosome, a complex of nucleases
involved in a number of different RNA processing reactions,
initially hinted at a role for SBDS in RNA metabolism. These
data are supported by studies in yeast, showing that depletion of
the SBDS ortholog SDO1 (also known as YLR022c) interferes
with the processing of the 35S rRNA primary transcript.50 In the
initial screening experiments, which involved a panoramic view
of yeast mutants involved in RNA metabolism using regulated
promoter alleles to silence expression of selected genes, the
SDO1 mutants exhibited a so-called processome-like pheno-
BLOOD, 15 JUNE 2006 䡠 VOLUME 107, NUMBER 12
type.50 This is characterized by inefficient cleavage of the
primary rRNA transcript within the 5⬘ external transcribed
sequence (ETS) and ITS1 sites, which in turn should lead to a
defect in 40S subunit maturation, similar to that seen with
defects in RPS19 (Figure 2). Although our own preliminary
experiments confirm inefficient cleavage of the primary rRNA
transcript,51 the exact molecular function of the SBDS orthologs
is likely to be more complex than initially believed and involve
the 60S ribosomal subunit as well. In this regard, tagged Sdo1
copurified with over 20 proteins involved in ribosome biosynthesis, including components of the 60S subunit.8 The finding that
the human SBDS protein is localized to the nucleolus further
supports a role for this protein in ribosome synthesis.52 More
detailed studies on the function of SBDS will be necessary to
clarify this specific function. As noted for the other bone marrow
failure gene products under discussion here, it would not be
surprising to find extraribosomal functions for SBDS as well.
Treacher Collins syndrome: severing the
ribosome synthesis/bone marrow failure link?
Treacher Collins syndrome (TCS), an autosomal dominant disorder
of craniofacial development, is caused by mutations in the TCOF1
gene, which encodes a nucleolar phosphoprotein called treacle
(Table 1). Treacle has been shown to affect ribosomal DNA
transcription by interacting with upstream binding factor, an RNA
polymerase I transcription factor53 (Figures 1-2). In addition,
treacle plays a role in pre-rRNA methylation.54 Haploinsufficiency
of treacle in TCS disrupts ribosome synthesis in a manner
reminiscent of that observed in dyskerin mutants, which also affect
rRNA modification. Yet TCOF1 mutants lead to abnormal proliferation and/or differentiation of neural crest precursor cells involved
in craniofacial development without interfering with hematopoiesis. A subset of DBA patients, who as a group appear to lack
RPS19 mutations, presents with craniofacial abnormalities indistinguishable from those seen in TCS.55,56 Thus, mutations in as yet
unidentified DBA genes may give rise to ribosomal defects
reminiscent of TCOF1 haploinsufficiency, manifesting during
embryogenesis and again during erythroid development.
These results, together with the foregoing discussion, suggest
that defects in factors involved in ribosome synthesis affect tissues
in different highly specific ways that are difficult to predict.
Clearly, many questions remain unanswered regarding the bone
marrow failure–ribosome synthesis link. It will be important to
determine if the consequences of disrupting the function of
ribosome synthesis factors result from quantitative changes in
protein synthetic capacity in a tissue-specific manner or instead a
differential sensitivity of certain cell lineages to a general reduction
in protein synthetic capacity. Only further experiments will be able
to resolve these critical issues.
Defects in ribosome synthesis:
the cancer connection
Mutations in genes involved in each of the diseases discussed have
the potential to perturb the synthesis of ribosomal subunits and, as
such, fundamentally alter the protein synthetic capacity of cells.
Such alterations may also sensitize cells to apoptotic stimuli,
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BLOOD, 15 JUNE 2006 䡠 VOLUME 107, NUMBER 12
RIBOSOMES AND MARROW FAILURE
accelerating programmed cell death pathways. Recent evidence
suggests that cytopenias in many, if not all, of the bone marrow
failure syndromes may be a consequence of accelerated apoptotic
death of hematopoietic progenitor cells.57-64 A possible explanation
for this apoptotic sensitivity relates to the activation of the p53
tumor suppressor. It has been postulated that disturbances in
ribosome synthesis must be detected and coupled with cell cycle
arrest in order to prevent aberrant cell divisions. Hence, close
coordination exists between p53-mediated cell growth regulation
and cellular responses to malfunction of ribosome synthesis.
Normally, ribosomal biogenesis is coordinated by growth signals.65
The tumor suppressors p53,66,67 the RB retinoblastoma protein,68-70
and p19ARF71 have all been shown to interfere with rRNA
synthesis or processing, thereby controlling ribosomal biogenesis.
Overproduction of these tumor suppressors inhibits protein synthesis while arresting cell growth in response to stress signals.
Apparently, p53 can also sense perturbations in ribosomal biogenesis, as from defects in rRNA synthesis and processing or
disruption of ribosome assembly.72,73 Therefore, disruption of
ribosomal biogenesis (and resulting “nucleolar stress”13) should
lead to p53 activation and oppose oncogenic transformation.74-76
While this may contribute to the proliferative defects in bone
marrow failure, how might leukemia or nonhematopoietic cancer
evolve? Presumably, for leukemia, there is strong selective
pressure for clonal outgrowth of cells with mutations that can
compensate for the “ribosome-depleted” state. One way to
increase ribosome synthesis would be to overexpress the Myc
oncoprotein,77 a major regulator of ribosome-related genes, or to
inactivate RB, which dampens RNA polymerase I. For nonhematopoietic cancers as are seen in DBA,78 mutations in ribosomal
genes may be directly oncogenic as suggested by the recent finding
that heterozygous mutations in several zebrafish ribosomal protein
genes induce tumors.79
4587
Concluding remarks
In this “Perspective,” we have attempted to critically appraise the
hypothesis that defects in ribosomal biogenesis underlie bone
marrow failure. At present, the ribosome/marrow failure association does not seem to rise to the level of a molecular paradigm.
Treacher Collins syndrome and anauxetic dysplasia demonstrate
that defects in ribosome synthesis can cause clinical syndromes
that do not include bone marrow failure. Moreover, the pathologies
observed in X-linked DC and CHH appear to be predominantly
consequences of extraribosomal functions of each affected gene
product. In these latter examples, however, associated defects in
ribosome synthesis may serve as important disease modifiers
(Figure 1). In this context, defects in ribosome synthesis may
enhance disease severity by compounding the effects mediated
through the extraribosomal functions or by expanding the range of
clinical manifestations by affecting additional tissue types. These
data also do not exclude defects in ribosome synthesis as a primary
cause for other bone marrow failure syndromes such as DBA and
SDS. Regardless of whether factors that affect ribosome synthesis
are a principal determinant or a modifier of disease severity in the
bone marrow failure syndromes, novel therapeutic strategies aimed
at restoring ribosomal function in hematopoietic cells may prove
useful in treating cytopenias. Finally, components of the ribosomal
pathway may represent targets for cancer treatment, which may
break the vicious cycle between marrow failure and cancer
predisposition.
Acknowledgments
We thank Drs Jeffrey Lipton and Amy Massey for critically
reviewing the manuscript.
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2006 107: 4583-4588
doi:10.1182/blood-2005-12-4831 originally published online
February 28, 2006
Ribosomes and marrow failure: coincidental association or molecular
paradigm?
Johnson M. Liu and Steven R. Ellis
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