The Genetics of the Myelodysplastic Syndromes: The Hunt for Candidate Genes
Harold J. Olney, M.D., C.M., and Michelle M. Le Beau, Ph.D.
University of Chicago
Section of Hematology/Oncology
The myelodysplastic syndromes are a collection of 5 clinico-pathologic entities with a wide spectrum
of clinical behavior and survival. Cytogenetic and molecular analyses have been instrumental in (1)
refining the prognosis; (2) predicting the likelihood of progression to acute myeloid leukemia; (3)
predicting the median survival; (4) establishing clonality of these diseases; and 5 clarifying of some
of the pathobiological processes involved in the genesis of these entities. This review highlights the
most frequent abnormalities and summarizes their clinical and genetic features.
At the time of diagnosis, recurring chromosomal abnormalities are found in 40-70% of patients with
primary MDS and in 95% of patients with therapy-related MDS (t-MDS).1-6 The frequency of cytogenetic
abnormalities increases with the severity of the disease and the risk of leukemic transformation, ranging
from 15-20% of cases in refractory anemia (RA) and refractory anemia with ring sideroblasts (RARS) to 75%
in refractory anemia with excess blasts (RAEB) and refractory anemia with excess blasts in transformation
(RAEB-t). The abnormal clones may evolve with disease progression, and typically resolve following
treatment with remission of disease. The most common cytogenetic abnormalities encountered in MDS are
del(5q), -7, and +8 (Table 1), which have been included in subsequent prognostic scoring systems of MDS.
Clones with unrelated abnormalities, one of which typically has a gain of chromosome 8, are seen at a
greater frequency (~5% vs. ~1%) in patients with MDS than acute myeloid leukemia (AML). Among the few
independent variables identified that predict clinical outcomes in MDS, cytogenetic findings form the
cornerstone of successful prognostic scoring systems.7
The new World Health Organization (WHO) classification requires cytogenetic data for diagnostic
purposes; thus, cytogenetic analysis will be a mandatory step in the full evaluation of a newly diagnosed
patient.8, 9 This proposal eliminates refractory anemia with excess blasts in transformation (RAEB-t),
redefining them as AML, reclassifies chronic myelomonocytic leukemia (CMMoL) as a hybrid between MDS and
myeloproliferative diseases (MPD), separates the 5q- Syndrome as a distinct MDS entity, and introduces
the new entity of refractory cytopenias with multi-lineage dysplasia (RCMD).
In general, the recurring abnormalities found in MDS are unbalanced, with chromosome loss and deletion
as well as unbalanced translocations commonly observed (Table 1). Although less common, recurring
balanced translocations have been reported in some cases. A few specific cytogenetic abnormalities have
been recognized that are closely associated with morphologically and clinically distinct subsets of MDS,
including the 5q- syndrome,10 the 17p- syndrome (11), and the isodicentric X chromosome associated
with RARS with a high likelihood of transformation to AML. Other abnormalities such as the t(15;17),
inv(16) and t(8;21) are usually restricted to acute leukemia.2, 5, 6 The t(9;22) is characteristic of
chronic myelogenous leukemia and a subtype of acute lymphoblastic leukemia, but has only rarely been
reported in MDS. Many other findings, including loss or deletions of chromosomes 5 or 7, trisomy 8, and
complex karyotypes, are common to both MDS and AML, including the new RCMD subtype of the WHO
classification. The detection of one of these recurring abnormalities can be quite helpful in
establishing the correct diagnosis, and can add information of prognostic importance permitting tailored
treatment planning. Serial evaluations can also be informative, particularly when there is a change in
the clinical picture. The identification of new abnormalities in the karyotype often signals a change in
the pace of the disease, usually to a more aggressive course, and may herald incipient leukemia.
The International MDS Risk Analysis Workshop combined cytogenetic, morphologic, and clinical data from
seven large risk-based studies to describe an International Prognostic Scoring System (IPSS) for MDS.7 The
IPSS combines cytogenetic abnormalities (outlined in Table 2), percentage of marrow blasts, and
number of peripheral cytopenias to define three risk groups: good, intermediate and poor outcome, with a
median survival of 3.8, 2.4 and 0.8 years, respectively. The IPSS has been found to be highly
reproducible in predicting survival and risk of leukemic transformation.5, 12 Karyotypic evolution in
MDS is associated with a transformation to acute leukemia in about 60% of cases, and reduced survival,
particularly for those patients who evolve within a short period of time (less than 100 days).13
Molecular Models for Chromosome Abnormalities in MDS
As described earlier, many of the recurring chromosomal abnormalities in MDS lead to the loss of genetic
material. Loss of genetic material is the hallmark of tumor suppressor genes, which normally function to
control cell growth and/or cell death by regulating the cell cycle, the response to DNA damage, and
A simple "two-hit" model involving a single target tumor suppressor gene (Knudson's model) predicts
that loss of function of both alleles must occur for manifestation of the malignant phenotype.14 Loss
of gene function may occur in a number of ways, including chromosomal loss or deletion, point mutations,
or by transcriptional silencing via methylation of the control elements of the gene. In t-AML, a
relatively long latency period between the time of exposure and bone marrow dysfunction in many of these
patients is compatible with a two-step mechanism in which two mutations of a target gene must occur in a
myeloid progenitor cell. These patients may have two normal alleles at the tumor suppressor gene locus
initially, one of which is mutated as a result of therapy. Subsequent loss of the second allele in a
bone marrow stem cell would permit leukemia development. The cytotoxic therapy may induce visible
chromosomal abnormalities or submicroscopic mutations (or both) in bone marrow cells of t-AML patients.
Alternatively, because AML develops in only 5-15% of patients who are treated for a primary tumor, these
individuals may have inherited a predisposing mutant allele; subsequent exposure to cytotoxic therapy may
induce the second mutation, giving rise to leukemia. In these cases, characterization of the
predisposing mutations will be important in identifying individuals who are at risk of developing t-AML,
and in the selection of the appropriate therapy for the primary malignant disease.
In an alternative model, loss of only a single copy of a gene may result in a reduction in the
level of one or more critical gene products (haploinsufficiency). Several recent reports implicate
haploinsufficiency of the TP53 and p27Kip1
genes in the pathogenesis of tumors in mice, where a substantial percentage of tumors retain a functional
copy of TP53 or p27Kip1. In humans,
haploinsufficiency of the RUNX1 (runt-related transcription factor 1, also
known as AML1) gene results in a familial platelet disorder with a
predisposition to AML.15 Importantly, the few leukemias available for analysis from affected family
members appear to retain one normal RUNX1 allele. With respect to the
deletions of 5q, 7q and 20q in MDS and AML, homozygous deletions have not been detected, an observation
that is compatible with a haploinsufficiency model in which loss of one allele of the relevant gene (or
genes) perturbs cell fate. However, the presence of one or more genes required for cell viability in
close proximity to a tumor suppressor gene locus may preclude the existence of large homozygous
structural deletions. At present, there is little experimental evidence favoring one or the other of
these alternative models in the pathogenesis of MDS.
Cytogenetic Subgroups in MDS
Between 30 and 60% of patients with MDS have a normal karyotype. It is likely that this subgroup is
heterogeneous, consisting of patients in whom the genetic alterations responsible for neoplastic
transformation are not detectable by standard cytogenetic methods, or in whom chromosomally abnormal
cells were not detected due to technical factors. Regardless of the etiology, these cases are found to
have a better prognosis than some cases of MDS with cytogenetic abnormalities, and are a reference for
comparison of outcomes.7 The median survival for these good prognosis patients is 3.8 years, and the
time to progression to AML of 25% of this cohort was 5.6 years.7
A deletion of the long arm of chromosome 20, del(20q), is a common recurring abnormality in malignant
myeloid disorders. Although initially described in polycythemia vera, it was soon detected in other
myeloid disorders including MDS, AML, and other myeloproliferative disorders.16 The abnormality is
seen in approximately 5% of MDS cases and 7% of t-MDS cases.6
A number of consistent features have been described in MDS patients with a del(20q), including
low risk disease (usually RA), low rate of progression to AML, and prolonged survival (median of 45
months vs. 28 months for other MDS patients).17 Morphologically, the presence of a del(20q) is
associated with prominent dysplasia in the erythroid and megakaryocytic lineages.18 The International
MDS Risk Analysis Workshop found that patients with a del(20q) observed in association with a complex
karyotype identified a poor-risk group with a median survival for the entire poor risk group of 9.6
months, whereas the prognosis for patients with an isolated del(20q) was favorable.7 Taken together,
these data suggest that the del(20q) in MDS may be associated with a favorable outcome when noted as the
sole abnormality, but with a less favorable prognosis in the setting of a complex karyotype. This
phenomenon is analogous to that observed for the del(5q) in MDS (discussed below).
Cytogenetic analysis of the deleted chromosome 20 homologs has revealed that the deletions are
variable in size; the majority of deletions are large with loss of most of 20q. By using fluorescence
in situ hybridization (FISH) with a panel of probes from 20q, combined with
loss of heterozygosity (LOH) studies, investigators have identified an interstitial commonly deleted
segment (CDS) within 20q12 that is flanked by D20S206 on the proximal side, and D20S424 on the distal
side. This CDS is ~4 Mb and is gene-rich.19, 20 At present, the identity of a myeloid tumor
suppressor gene on 20q is unknown. Several research groups have identified interesting candidate genes
by generating a detailed physical map as well as a transcriptional map of the CDS.19, 20 The
functions of candidate genes within the CDS are diverse, and include transcription factors, components
of signal transduction pathways, an RNA transcription modulator and a regulator of apoptosis.19
The clinical and biological significance of the loss of the Y chromosome, -Y, is unknown. Loss of the
Y chromosome has been noted in a number of malignant diseases, but has also been reported to be a
phenomenon of aging.21 The United Kingdom Cytogenetics Group undertook a comprehensive analysis of
this abnormality in both normal and neoplastic bone marrows.22 They found that a -Y could be
identified in 7.7% of patients without a hematologic malignant disease and in 10.7% of patients with MDS
and, thus, could not be used to document a malignant process. The International MDS Risk Analysis
Workshop found that while loss of a Y chromosome may not be diagnostic of MDS, once the disease is
identified by clinical and pathologic means, -Y as the sole cytogenetic abnormality conferred a favorable
outcome.7 More recently, Wiktor et al. reported on a large series of 215
male patients, and found that patients with a hematological disease had a significantly higher percentage
of cells with a Y (52% vs. 37%, p = 0.036). In this series, the presence of Y in > 75% of
metaphase cells accurately predicted a malignant hematologic disease.21 The authors also noted a
neutral or favorable prognosis for an isolated Y.
Loss of chromosome 5 or del(5q)
Loss of a whole chromosome 5, or a deletion of the long arm of this chromosome, -5/ del(5q), are
observed in 10-20% of patients with a MDS or AML arising de novo, and in 40%
of patients with t-MDS/t-AML (Table 4).6, 23 Notably, many patients with AML or MDS de novo and either 5/del(5q) or a 7/del(7q) have a significant occupational
exposure to potential carcinogens, suggesting that abnormalities of chromosome 5 or 7 may be a marker of
mutagen-induced malignant hematologic disease.24
In primary MDS, abnormalities of chromosome 5 are observed in the 5q- Syndrome or in RAEB or RAEB-t in
association with a complex karyotype. Clinically, the patients with del(5q) and additional cytogenetic
abnormalities have a poor prognosis with early progression to leukemia, treatment resistance, and short
survival. Abnormalities of 5q are associated with previous exposure to standard and high dose alkylating
agent therapy, including use in immunosuppressive regimens 23-26 (Table 5). A role for exposure to
benzene 26 as well as therapeutic ionizing radiation as risks for MDS is emerging.
The identification of a del(5q) as the sole karyotypic abnormality is associated with a distinct
clinical syndrome.9, 10, 27 This syndrome features an over representation of females (2:1), which is
in contrast to the male preponderance of MDS in general. The initial findings are usually a macrocytic
anemia, and a normal or elevated platelet count. The diagnosis is usually RA (in two-thirds), or RAEB
(in one-third). The presence of abnormalities in the megakaryocytic lineage (particularly
micromegakaryocytes) is the predominant finding in the bone marrow. These patients have a favorable
outcome, in fact the best of any MDS subgroup, with low rates of leukemic transformation and a relatively
long survival of several years duration.7, 27
Molecular analysis of the del(5q)
Several groups of investigators have defined a CDS on the long arm of chromosome 5 (Figure 1).28-31
It is predicted that this CDS contains a myeloid tumor suppressor gene. By cytogenetic and
FISH analysis of 177 patients with de novo MDS/AML or t-MDS/t-AML, Le Beau
and colleagues defined a 1.5 Mb CDS within 5q31 flanked by D5S479 and D5S500.29 To identify candidate
tumor suppressor genes, they developed a transcript map of the CDS, which contains 20 known genes and a
number of expressed sequence tags (ESTs).29 The function of these genes covers a spectrum of
activities including regulation of mitosis and the G2 checkpoint, transcriptional and translational
regulators, and cell surface receptors. Analysis of myeloid leukemia cells for inactivating mutations
has eliminated the 20 genes within the CDS as classical tumor suppressor genes, suggesting that a novel
myeloid tumor suppressor gene located in this interval might be involved in the pathogenesis of these
disorders.29, 31 and Le Beau unpublished data
Molecular analysis of the del(5q) in patients with the 5q- Syndrome suggests that a different region,
and hence a different gene, is involved. Boultwood and colleagues examined three patients with the 5q-
Syndrome with small deletions extending from 5q31-33, and identified a 3 Mb CDS within 5q33 between ADRB2 and IL12B.32 This region is distal to the
CDS in 5q31 found in the patients with RAEB, RAEB-t and AML with del(5q). Whether all patients with the
5q- Syndrome have involvement of a gene in this distal region, and whether this gene plays a role in the
pathogenesis of other subtypes of MDS or AML is unknown.
In summary, the existing data suggest that there are two non-overlapping CDS in 5q31 and 5q33. The
proximal segment in 5q31 is likely to contain a tumor suppressor gene involved in the pathogenesis of
both de novo and therapy-related MDS/AML. Band 5q33 is likely to contain a
second myeloid tumor suppressor gene involved in the pathogenesis of the 5q- Syndrome.
Loss of chromosome 7 or del(7q)
A 7/del(7q) is observed as the sole abnormality in approximately 5% of patients with de novo MDS 4, 5 and in approximately, 55% of patients with t-MDS.23 It can
occur in three general contexts (1) de novo MDS and AML; (2) myeloid
leukemia associated with constitutional predisposition; and (3) t-MDS/t-AML.33 The similar clinical
and biological features of the myeloid disorders associated with 7/del(7q) suggest that the same gene(s)
is altered in each of these contexts. An entity designated "Monosomy 7 Syndrome" has been described in
young children. It is characterized by a preponderance of males (~4:1), hepatosplenomegaly,
leukocytosis, thrombocytopenia, and poor prognosis.34 Juvenile myelomonocytic leukemia (JMML,
previously known as juvenile chronic myelogenous leukemia) shares many features with this entity, and
bone marrow examination from patients with JMML often reveals -7 either at diagnosis or as a new
cytogenetic finding associated with disease acceleration.33 A -7/del(7q) is the most frequent
cytogenetic abnormality detected in the bone marrow of patients with constitutional predispositions to
myeloid neoplasms, including Fanconi anemia, neurofibromatosis type 1, and severe congenital
neutropenia. As with 5/del(5q), occupational or environmental exposure to mutagens including
chemotherapy, radiotherapy, benzene exposure, and smoking as well as severe aplastic anemia (regularly
treated with immunosuppressive agents alone) have been associated with 7/del(7q).24-26
Molecular analysis of the 7/del(7q)
As with the 5/del(5q), investigators have examined the breakpoints and extent of the deletions of 7q
in patients to identify a CDS (Figure 2).35-40 Le Beau et al., examined
81 patients with de novo or t-MDS/t-AML, and identified two distinct CDSs.
In 65 patients, the CDS was within q22, whereas in 16 other patients, interstitial deletions of a more
distal segment were detected with a CDS of q32-33.36 FISH identified an ~2 Mb CDS in 7q22, a finding
that is consistent with most published data.36-40 Tosi et al. evaluated
patients with 7q abnormalities and identified an interesting patient with a complex karyotype and a
t(7;7) who had a deletion associated with the translocation breakpoint of 150 kb proximal to the CDS
defined by Le Beau et al. .38 A number of candidate genes have been
identified and evaluated for mutations within the CDS at 7q22 including extracellular (or
extracellular-like) proteins, replication and transcriptional control elements, a splicing factor kinase
and a mitochondrial processing peptidase.41 None have disclosed mutations in the remaining allele.
Data from cytogenetic, FISH and LOH studies performed in a number of laboratories paint a complex
picture of 7q deletions in myeloid malignancies. There is general agreement that 7q22 is involved in a
majority of cases. Defining a consistent CDS has been complicated by (1) the relatively low frequency of
del(7q) versus complete loss of chromosome 7; (2) the use of different techniques to investigate marrow
samples, e.g., FISH vs. LOH; (3) the wide spectrum of myeloid disorders with alterations in chromosome
7, suggesting genetic heterogeneity; and (4) the existence of multiple and sometimes complex cytogenetic
abnormalities in some cases.
Abnormalities resulting in the loss of the short arm of chromosome 17 (17p-) have been reported in up
to 5% of patients with MDS.42 These include simple deletions, unbalanced translocations, dicentric
rearrangements (particularly with chromosome 5), or less often -17, or isochromosome formation. A
frequent recurring rearrangement is the dic(5;17)(q11-13;p11-13).42, 43 Approximately one-third of
these patients have t-MDS,44 and most have additional cytogenetic abnormalities. The most common
additional changes are unbalanced translocations involving chromosomes 5 or 7.
Morphologically, the 17p- syndrome is associated with a typical form of dysgranulopoiesis combining
pseudo-Pelger-Huet hypolobulation and the presence of small granules in granulocytes. Clinically, the
disease is aggressive with resistance to treatment and short survival. The TP53 (p53) gene, an important tumor suppressor gene that functions to arrest cell
cycling after DNA damage, is located at 17p13.1. One allele of TP53 is
typically lost as a result of the abnormality of 17p in these cases; an inactivating mutation in the
second allele on the remaining, normal chromosome 17 occurs in ~70% of cases.42, 43 Sankar et al. mapped a CDS in leukemia and lymphoma patients to 17p13.3, suggesting the
existence of a novel tumor suppressor gene distal to TP53.45
The MLL (Mixed Lineage Leukemia) gene (also known as ALL1, Htrx, HRX) is involved in over 45 reciprocal translocations in acute
leukemia (46). In a recent European workshop of 550 patients with 11q23 abnormalities, 28 cases (5.1%)
presented with a MDS and five others had evolved from t-MDS to t-AML prior to cytogenetic study,
accounting for up to 6% of the total cases examined. A quarter of these cases were t-MDS.47 In both
de novo and t-MDS, the 11q23 abnormalities were frequently accompanied by
additional abnormalities including complex karyotypes and 7/del(7q). No association with FAB subgroup
was identified, but RA was over-represented, and RARS underrepresented as compared to most series of MDS
patients. The median survival was short (19 months) with leukemic transformation in ~ 20% of cases.
This workshop did not find the classic association of prior exposure to topoisomerase II inhibitors in
their 40 cases of t-MDS and t-AML, but this may simply reflect the relatively small number (n=23) of
cases with full treatment details.48
An International Workshop on Leukemia Karyotype and Prior Treatment held in June 2000, evaluated 511
patients with t-MDS/t-AML and balanced chromosomal aberrations, such as translocations (25-33% of all
t-MDS/t-AML cases). Just under 12% of the 162 patients with 11q23 involvement presented with a t-MDS .49
One third (6/19) of these patients had progression to an acute leukemia (5 AML, 1 ALL). No clear
association with FAB subtype was identified. The most common translocations were t(9;11) in 5 cases;
t(11;19) in 4 cases (three involved 19p13.1), and t(11;16) in 3 cases.
The incidence of a gain of chromosome 8 in MDS is ~10%. This abnormality is observed in all FAB
subgroups.2, 6, 7 The significance of the gain of chromosome 8 in MDS patients is not fully
characterized as a risk factor. The situation is complicated in that +8 is often associated with other
recurring abnormalities known to have prognostic significance, and may be seen in isolation as a separate
clone unrelated to the primary clone in up to 5% of cases. The International MDS Risk Analysis Workshop
ranked this abnormality in the intermediate risk group.7
Complex karyotypes have been variably defined, but generally involve the presence of >
three abnormalities. The majority of cases with complex karyotypes involve unbalanced chromosomal
abnormalities leading to the loss of genetic material. Complex karyotypes are observed in ~20% of
patients with primary MDS, and in as many as 90% of patients with t-MDS.23, 50 Abnormalities
involving chromosomes 5, 7, or both are identified in most cases with complex karyotypes. There is
general agreement that a complex karyotype carries a poor prognosis.7
The evolution in management of oncology has dramatically improved the survival of some cancer
patients, who now survive the acute toxicities of therapy, and develop late toxic complications.
Techniques in supportive care, including stem cell transplantation, have reduced the once lethal
complications of these treatment strategies, and have permitted not only dose escalation, but have also
allowed the testing of significantly more toxic agents and combinations of agents. One of the most
serious consequences of cancer therapy is the development of a second cancer of myeloid origin. In
patients treated with high dose therapy for breast cancer, lymphoma, leukemias and multiple myeloma, the
reported incidences of t-MDS/t-AML is 1-24% of treated patients.25 Increasing numbers of patients
with benign disease, particularly rheumatology and dermatology patients as well as organ transplant
recipients, are also being exposed to cytotoxic agents for immunosuppression, placing them at risk for
some of the same late complications.
Cytogenetic aberrations are detected in up to 90% of patients with t-MDS.23, 50 Several
clinical-morphologic-cytogenetic subsets of t-MDS/t-AML have been identified, which are closely
associated with the type of prior therapy (Table 5).23, 51 The patients exposed to alkylating agents
typically have a longer latency period to bone marrow dysfunction (median 5-7 years), and develop t-MDS
with trilineage dysplasia, which often progresses to t-AML. Abnormalities of chromosomes 5, and/or 7,
and complex karyotypes predominate. Patients exposed to topoisomerase II inhibitors are more likely to
present with t-AML, have a shorter latency period, generally within 2 years, and have abnormalities
involving MLL at 11q23 or RUNX1 (AML1) at 21q22.23, 51
Expression profiling of CD34+ hematopoietic progenitor cells from t-MDS/t-AML patients
revealed that there are distinct subtypes of t-AML that have a characteristic gene expression pattern .52
Common to each of the subgroups are gene expression patterns typical of arrested differentiation
in early progenitor cells. ). t-AML patients with abnormalities of chromosomes 5 or 7 have similar
clinical and morphological features. Surprisingly, these patients did not cluster into the same group.
Patients with a 5/del(5q) have a higher expression of genes involved in cell cycle control (CCNA2, CCNE2, CDC2),
checkpoints (BUB1), or growth (MYC), and loss
of expression of the gene encoding interferon consensus sequence binding protein (ICSBP), a regulator of hematopoiesis. A second subgroup of t-AML, including
patients with normal karyotypes, is characterized by down-regulation of transcription factors involved in
early hematopoiesis (TAL1, GATA1, and EKLF),
and overexpression of proteins involved in signaling pathways in myeloid cells (FLT3), and cell survival
(BCL2). Establishing the molecular pathways involved in t-AML may facilitate the identification of
selectively expressed genes that can be exploited for the development of urgently needed targeted
Rare recurring translocations
The identification of genes involved in recurring cytogenetic abnormalities has been extremely useful
in gaining insights into their normal functions and their role in leukemogenesis.46, 53 The
consequence of the recurring translocations is the deregulation of gene expression with increased
production of a normal protein product, or the generation of a novel fusion gene, and production of a
fusion protein. In MDS, several such translocations have been identified and examined by molecular
The t(5;12)(q33;p12) is observed in ~1% of patients with CMMoL. The gene encoding the beta chain of
the platelet derived growth factor receptor (PDGFRB) is involved on
chromosome 5. A novel ETS-like (Erythroblastosis virus Transforming Sequence) transcription factor,
ETV6/TEL, is the gene affected on chromosome 12. The translocation creates
a fusion gene and fusion protein containing the 5' portion of TEL and the 3'
portion of PDGFRB.54 It is believe that the PDGFRB kinase activity is
perturbed resulting in the transformed phenotype. TEL encodes a
transcriptional repressor, and is promiscuously involved in translocations with some 40 genes in
The t(3;21)(q26.2;q22.1) has been linked to acute leukemia arising after cytotoxic therapy. This
abnormality was first recognized in chronic myelogenous leukemia in blast crisis and later in t-MDS/t-AML .55
The EAP gene (Epstein-Barr small RNAs Associated Protein) at 3q26.2
encodes a highly-expressed small nuclear protein associated with EBV small RNA (EBER1). EAP was found to be fused with the RUNX1 gene at
21q22, retaining the DNA binding sequences of EAP. The fusion is
out-of-frame so that the RUNX1 gene is truncated and loses its functional
activity. Further work has identified two additional genes 400-750 kb centromeric to EAP, also at 3q26.2,namely MDS1/EVI1 (MDS associated
sequences) and EVI1 (Ecotropic Virus Insertion site).reviewed in 56 Both
genes encode nuclear transcription factors containing DNA-binding zinc finger domains, which are
identical other than an N-terminal extension of 12 amino acids in the MDS1/EVI1 protein, representing a
splicing variant. Each gene has independent and tightly controlled expression during differentiation.
The MDS1/EVI1 and EVI1 proteins have opposite functions. EVI1 inhibits G-CSF-mediated differentiation
and the growth-inhibitory effect of TGFb1, whereas MDS1/EVI1 has no effect on G-CSF and enhances TGF b1
growth-inhibition. RUNX1 fuses with MDS1/EVI1,
in frame, resulting in the loss of the first 12 amino acids, producing a novel EVI1 protein, and a
phenotype of arrested differentiation which leads to apoptosis in vitro.56
Among over 45 recurring translocations of MLL in myeloid neoplasms (with
AML predominating), the t(11;16) (q23;p13.3) is unique in that most patients have t-MDS.57 The MLL gene on chromosome 11 is fused with CBP (CREB
binding protein gene) on chromosome 16.57 The MLL protein is likely to be multifunctional, and is
known to regulate HOX gene expression during development. CBP is an adapter
protein involved in transcriptional control via histone acetylation, which mediates chromosome
decondensation, thereby facilitating transcription. Both genes have multiple translocation partners in
various hematologic disorders, and elucidating their multiple functions will undoubtedly lead to
significant progress in leukemia research.
Alterations in gene function
The most extensively studied gene family in MDS is the RAS family. RAS proteins are a critical
component of signaling pathways leading from cell-surface receptors to the nucleus, and resulting in the
control of cellular proliferation, differentiation, and cell death. These proteins bind guanine
nucleotides, and their function is controlled by cycling between the guanosine triphosphate bound
(active) and guanosine diphosphate bound (inactive) forms.58 Once activated by a cell surface
receptor, RAS proteins induce a cascade of kinase activity, resulting in the transduction of the signals
to the nucleus. Mutant RAS proteins retain the active GTP-bound form, promoting constitutive
activation. The most frequent mutation is a single base change at codon 12 of the protein, but codons 13
and 61 are also frequently mutated. Codons 12 and 13 are located within the pocket that binds GTP, and
mutant proteins have decreased phosphatase activity, which normally reverts RAS to the inactive GDP
form. A wide variety of human malignancies have been found to harbor mutations in RAS genes.58 Constitutively activating point mutations of NRAS have been detected at high frequency in hematologic malignancies. In MDS,
NRAS mutations have been detected in 10-40% of cases. These mutations have
been associated with a poor prognosis with higher incidence of transformation to AML and shorter
survival. Those patients with both abnormal karyotypes and NRAS mutations
have the highest likelihood of transformation.59-62
There is a growing body of evidence suggesting that mutations of multiple genes mediate the
pathogenesis and progression of MDS. Table 3 provides a partial list of the involved genes and summary
of some of their salient features related to MDS.
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TABLE 1. RECURRING CHROMOSOMAL ABNORMALITIES IN PRIMARY MDS
|Unbalanced || Balanced |
| -7, del(7q), or unbalanced translocation of 7q ||5-10% ||t(1;3)(p36;q21.2) ||1%|
| -5, del(5q), or unbalanced translocations of 5q ||10-20% ||t(2;11)(p21;q23) ||<1%|
| del(17p), or unbalanced translocations of 17p ||7% ||t(6;9)(p23;q34) ||<1%|
| der(1;7)(q10;p10) ||1% ||t(5;12)(q33;p12) ||1% CMMoL|
| del(11q) || ||t(11q23) ||5-6%|
| del(12p) || || |
| del(13q) || || |
| del(20q) ||5% || |
| +8 ||10% || |
| +11 || || |
| -Y ||10% || |
Chromosomal breakpoints of the interstitial deletions of 5q are variable, but band q31 is invariably
deleted; proximal breakpoints frequently occur in bands 5q13-15 and distal breakpoints frequently occur
in bands q33-35.
q23.1 is always involved in either interstitial or terminal deletions.
Table 2. International Prognosis Scoring System.
25% AML progression
| || |
| || |
Table 3. Partial List of Genes Altered in MDS.
Overexpressed in all FAB subtypes
- encodes a protein product which suppresses apoptosis
- no correlation with survival
- highest levels in higher risk entities where apoptosis is reduced
Mutated in 12-20%, increased with higher risk MDS
- encodes the macrophage colony-stimulating factor receptor with tyrosine kinase activity
- karyotype predominantly normal
- increased frequency of transformation to AML and poor survival
Mutated (internal tandem duplication) in ~10% of MDS and AML with trilineage dysplasia
- encodes a class III receptor tyrosine kinase playing a role in stem cell differentiation
- internal tandem duplications cause constitutive activation
- associated with progression to AML and poor prognosis
- frequently observed with normal karyotype in AML
no mutations found
- encodes the stem cell factor receptor
- may provide an autocrine growth pathway
Expressed in ~60%
- encodes a transmembrane drug efflux pump
- may be involved in resistance of MDS to drug therapy
- associated with monosomy 7
Overexpressed in ~70 %
- encodes a protein product (murine double minutes-2) which targets the p53 tumor suppressor protein for ubiquitin-mediated degradation
- gene amplification not detected
- associated with unfavorable cytogenetic abnormalities
- shorter remission duration
Overexpressed in ~45% of CMMoL, and ~40% of RAEB, RAEB-t patients;
underexpressed (~50% of normal) in most MDS patients, especially RA
- encodes the thrombopoietin receptor
- higher expression in RAEB and RAEB-t associated with poor prognosis, increased progression to AML
- correlated with dysmegakaryocytopoiesis
Point mutations identified
- encodes the G-CSR receptor
- severe congenital neutropenia (SCN) patients with G-CSF receptor defects can progress to MDS and/or AML
- mutation alone is not sufficient for transformation
- progression to leukemia in SCN associated with loss of chromosome 7 and RAS mutations
Loss and mutations identified, particularly in pediatric MDS/MPS
- encodes neurofibromin, a tumor suppressor gene product, that functions as a GTPase activating (GAP) protein to downregulate RAS function
- high incidence of MDS and AML in children with neurofibromatosis type I
- no structural alteration in homologous allele in adults with loss of one chromosome 17
Mutated in 20-40%;
overexpressed in RA, RARS
- encodes a component of various cell surface signal transduction pathways
- activating mutations result in constitutive signaling
- associated with monocytic component
- increased risk of progression to AML
- overexpression may represent an early event in the multi-step process of transformation
telomerase (including hTERT, hTR, and TP1)
Increased activity late in disease, particularly hTERT
- enzyme complex responsible for chromosome telomere maintenance and replication
- variable levels of activity
- abnormal telomere maintenance may be an early indication of genetic instability
- telomeres shortened with disease progression
Mutated in 5-25%;
higher frequency in t-MDS
- encodes G1, S, and G2 checkpoint protein that monitors integrity of genome and arrests cell cycle in response to DNA damage,
- loss of wild type allele
- associated with weak BCL2 expression
- observed as both early and late genetic event in MDS
- associated with rapid progression and poor outcome
seen with loss of 17p, -5/del(5q), -7/del(7q) suggesting pathogenic exposure to carcinogens
FAB: French-American-British cooperative group
AML: acute myeloid leukemia
CMMoL: chronic myelomonocytic leukemia
RA: refractory anemia
RAEB: refractory anemia with excess blasts
RAEB-t: refractory anemia with excess blasts in transformation
RARS: refractory anemia with ring sideroblasts
Table 4. Cytogenetic Abnormalities in 306 Patients with
|Karyotype ||No. (%)|
|Normal karyotype || 24 (8)|
|Clonal abnormalities || 282 (92)|
| Clonal abnormalities of chromosomes 5 and/or 7 (may have additional abnormalities) ||214 (70)|
| Abnormal chromosome 5 only b || 63 (21)|
| Abnormal chromosome 7 only b || 85 (28)|
| Abnormal chromosome 5 and 7 || 66 (22)|
| Recurring balanced rearrangements || 31 (10)|
| t(11q23) || 10 (3.3)|
| t(21q22b || 8 (2.6)|
| t(15;17) || 6 (2.0)|
| inv(16) b || 6 (2.0)|
| t(8;16) || 1 (0.3)|
|Other clonal abnormalities ||39 (13)c|
a Ascertained at the University of Chicago between 1972-2002.
b One patient with an abnormality of chromosome 5 and the t(3;21), and one patient with
an abnormality of chromosome 7 and the inv(16) are listed twice in the table.
c Includes eight patients with +8, three patients with 13/del(13q), and one patient
each with del(20q), del(11q), +11, +21, or Y.
TABLE 5. SYNDROMES OF THERAPY-RELATED MYELODYSPLASTIC SYNDROME AND ACUTE MYELOID LEUKEMIA*
Type of Cytotoxic Agent(s) Received
Response to Induction Chemotherapy
Melphalan, mechlorethamine, chlorambucil, cyclophosphamide, carmustine, lomustine, semustine, procarbazine, dacarbazine, mitolactol
of 5q or 7q
M1, M2, M4
Typically older patients
Topoisomerase II inhibitor
Etoposide, teniposide actinomycin D, doxorubicin, 4 epi-doxorubicin, mitoxantrone
Less commonly: M1, M2 and ALL-L1 ||
6 mos - 5 yrs (median 2 yrs)
e.g., Bimolane or Radiation
FAB, French American British classification
MDS, myelodysplastic syndrome
RAEB, Refractory Anemia with Excess Blasts
RCMD, Refractory Cytopenias with Multilineage Dysplasia
* Adapted from ref no. 23.
Figure 1. Idiogram of the long arm of chromosome 5 showing chromosome markers and candidate genes
within commonly deleted segments (CDS) as reported by various investigators. The proximal CDS in 5q31
was identified in MDS, AML and t-MDS/t-AML, whereas the distal CDS in 5q33 was identified in the 5q-
Figure 2. Idiogram of the long arm of chromosome 7 showing chromosome markers and candidate genes
within commonly deleted segments (CDS) as reported by various investigators.