Myelodysplastic

Syndromes
Douglas C. Tkachuk MD, FRCPC
Kathy Chun PhD, FCCMG
Jan V. Hirschmann MD

Wintrobe's Atlas of Clinical Hematology, 1st Edition

Copyright 2007 Lippincott Williams & Wilkins

The myelodysplastic syndromes (MDSs):

are disorders caused by a clonal
expansion of hematopoietic stem cells
in which maturation is abnormal
(dysplastic) and production ineffective
resulting in many cells being destroyed
before they reach the systemic circulation

 Anemia typically occurs, often

accompanied by thrombocytopenia and/or
neutropenia
Some cases develop from exposure to
ionizing radiation or cytotoxic
chemotherapy, usually with alkylating
agents, and in these circumstances the
bone marrow is characteristically
hypocellular and partially fibrotic
More frequently, these diseases occur as
a primary problem in older adults, with a
median age of about 70 when diagnosed,
In them, the bone marrow is usually
hypercellular.

 Blasts may be increased in the

myelodysplastic syndromes, but they do
not exceed 20% of the differential count of
at least 200 leukocytes in the peripheral
blood and 500 in the bone marrow
Dysplasia may involve one or more
hematopoietic lines; to be significant it
should affect at least 10% of that line's
cells in the bone marrow, but evidence for
dysplasia may also be present on the
peripheral smear

 Evidence of abnormal granulopoiesis on

peripheral smear includes neutropenia,
hypersegmented neutrophils, Dhle
bodies, decreased or absent cytoplasmic
granules, and the presence of immature
cells, including blasts.
The nuclei may have dense chromatin
clumping, and many are hypolobulated,
with a single lobe or two joined by a thin
band of chromatin, resembling the
congenital disorder, Pelger-Het
anomaly

 Refractory Anemia (RA)

Refractory Anemia with Ringed
Sideroblasts (RARS)
Refractory Cytopenia with Multilineage
Dysplasia (RCMD)
Refractory Anemia with Excess Blasts
(RAEB)
Myelodysplastic Syndrome, Unclassifiable
(MDS-U)
Myelodysplastic Syndrome Associated with
Isolated del(5q) Chromosome Abnormality
(5q- Syndrome)

 Abnormal thrombopoiesis on peripheral

smear is manifested by thrombocytopenia,
giant platelets, and those with decreased
or absent granules
In bone marrow specimens, dysplastic
megakaryocytes are small
(micromegakaryocytes), and possess
abnormal nuclei that are multiple and
widely separated or have decreased or
absent lobulation

Refractory Anemia (RA)

This entity accounts for about 5% to 10% of
cases of MDS, the median survival is about 5
years, and acute leukemia eventuates in
approximately 5% of patients.
Dysplasia occurs in the erythroid precursors
alone, ranges from mild to pronounced, and
consists of the findings described in the first
section.
On peripheral blood smear the red cells are
normocytic or macrocytic.
Nonspecific cytogenetic abnormalities occur in
about 25% of cases.

Refractory Anemia with Ringed

Sideroblasts (RARS)
This disorder is responsible for about 10%
of cases of MDS, has a median survival of
about 6 years, and has about a 1%
chance of evolving into acute leukemia
Dysplasia occurs only in the erythroid line,
and at least 15% of the red cell precursors
are ringed sideroblasts. Cytogenetic
abnormalities occur in <10% of cases

Refractory Cytopenia with Multilineage

Dysplasia (RCMD)
This disorder accounts for about 25% of MDS,
and the diagnosis requires cytopenias and
dysplastic changes in at least two lines
When, in addition, ringed sideroblasts constitute
>15% of the erythroid precursors, the diagnosis
is the subtype refractory cytopenia with
multilineage dysplasia and ringed sideroblasts
(RCMD-RS), which accounts for about 15% of
cases of MDS
The median survival for both is about 3 years,
and the risk of leukemia is approximately 10%.
Cytogenetic abnormalities occur in up to 50% of
cases

Refractory Anemia with Excess Blasts (RAEB)

In this MDS, the blasts are increased above normal, but
not sufficiently to meet the criteria for leukemia, which is
at least 20% of nucleated cells in the blood or bone
marrow
Two subtypes exist: RAEB-1 has 5% to 9% blasts in the
bone marrow and <5% in the blood; RAEB-2 has 10% to
19% blasts in the bone marrow and/or 5% to 19% blasts
in the blood. Those with Auer rods are also considered
RAEB-2
These two diseases account for approximately 40% of
cases of MDS
About 25% of RAEB-1 and 33% of RAEB-2 develop
acute leukemia, and their respective median survivals
are 18 and 10 months
Approximately 33% to 50% of these patients have
cytogenetic abnormalities

Myelodysplastic Syndrome, Unclassifiable

(MDS-U)
Patients are put in this category when they have
dysplasia restricted to either the neutrophil or
megakaryocytic lines
They fail to meet the criteria for the other MDSs
The number of patients who belong in this
group, their median survival, and the risk of
developing leukemia are uncertain

Myelodysplastic Syndrome Associated with Isolated del(5q)

Chromosome Abnormality (5q- Syndrome)
Unlike the other MDSs, this entity is primarily defined not
by hematologic findings but by a cytogenetic
abnormality, a deletion between bands q31 and 33 on
chromosome 5, with variability in the actual break points
and the size of the deletion
Most patients are middle-aged to older women, whose
major problem is refractory macrocytic anemia
Some patients have thrombocytosis. The bone marrow is
usually hypercellular, dysplasia is present in the erythroid
precursors, many megakaryocytes have hypolobulated
nuclei, and blasts are <5%
Patients typically have a long survival, and progression
to acute leukemia occurs in <25% of cases

TERIMA KASIH

RB Gene and Cell Cycle

RB exerts antiproliferative effects by controlling the G1to-S transition of the cell cycle. In its active form RB is
hypophosphorylated and binds to E2F transcription
factor
This interaction prevents transcription of genes like
cyclin E that are needed for DNA replication, and so the
cells are arrested in G1.Growth factor signaling leads to
cyclin D expression, activation of the cyclin D-CDK4/6
complexes, inactivation of RB by phosphorylation, and
thus release of E2F
Loss of cell cycle control is fundamental to malignant
transformation
Almost all cancers will have disabled the G1 checkpoint,
by mutation of either RB or genes that affect RB
function, like cyclin D, CDK4, and CDKIs
Many oncogenic DNA viruses, like HPV, encode proteins
(e.g., E7) that bind to RB and render it nonfunctional

p53 Gene: Guardian of the Genome

p53 is the central monitor of stress in the cell and can be
activated by anoxia, inappropriate oncogene signaling, or
DNA damage
Activated p53 controls the expression and activity of
genes involved in cell cycle arrest, DNA repair, cellular
senescence, and apoptosis.DNA damage leads to
activation of p53 by phosphorylation
Activated p53 drives transcription of CDKN1A (p21) that
prevents RB phosphorylation and therefore causes a
G1-S block in the cell cycle. This pause allows the cells
to repair DNA damage.If DNA damage cannot be
repaired, p53 induces cellular senescence or
apoptosis.Of human tumors, 70% have homozygous
loss of p53
Such individuals develop a variety of tumors.As with RB,
p53 can be incapacitated by binding to proteins encoded
by oncogenic DNA viruses like HPV, and possibly EBV
and HBV.

Evasion of Apoptosis
Apoptosis can be initiated through the extrinsic
or intrinsic pathways
Both pathways result in the activation of a
proteolytic cascade of caspases that destroys
the cell
Mitochondrial outer membrane permeabilization
is regulated by the balance between proapoptotic (e.g., BAX, BAK) and anti-apoptotic
molecules (BCL2, BCL-XL). BH-3-only
molecules activate apoptosis by tilting the
balance in favor of the pro-apoptotic molecules
In 85% of follicular B-cell lymphomas the antiapoptotic gene BCL2 is activated by the t(8;14)
translocation

Limitless Replicative Potential

In normal cells, which lack expression of
telomerase, the shortened telomeres generated
by cell division eventually activate cell cycle
checkpoints, leading to senescence and placing
a limit on the number of divisions a cell may
undergo
In cells that have disabled checkpoints, DNA
repair pathways are inappropriately activated by
shortened telomeres, leading to massive
chromosomal instability and mitotic crisis
Tumor cells reactivate telomerase, thus staving
off mitotic catastrophe and achieving immortality

Invasion and Metastasis

Ability to invade tissues, a hallmark of malignancy, occurs in four

steps: loosening of cell-cell contacts, degradation of ECM,
attachment to novel ECM components, and migration of tumor
cells.Cell-cell contacts are lost by the inactivation of E-cadherin
through a variety of pathways
Basement membranes and interstitial matrix degradation is
mediated by proteolytic enzymes secreted by tumor cells and
stromal cells, such as MMPs and cathepsins
Proteolytic enzymes also release growth factors sequestered in the
ECM and generate chemotactic and angiogenic fragments from
cleavage of ECM glycoproteins
The metastatic site of many tumors can be predicted by the location
of the primary tumor
Many tumors arrest in the first capillary bed they encounter (lung
and liver, most commonly)
Some tumors show organ tropism, probably due to expression of
adhesion or chemokine receptors whose ligands are expressed by
the metastatic site

Genomic Instability-Enabler of Malignancy

Individuals with inherited mutations of genes involved in DNA repair

systems are at a greatly increased risk of developing cancer
Patients with HNPCC syndrome have defects in the mismatch repair
system and develop carcinomas of the colon
These patients show microsatellite instability (MSI), in which short
repeats throughout the genome change in length
Patients with xeroderma pigmentosum have a defect in the
nucleotide excision repair pathway and are at increased risk for the
development of cancers of the skin exposed to UV light, because of
an inability to repair pyrimidine dimers
Syndromes involving defects in the homologous recombination DNA
repair system compose a group of disorders (Bloom syndrome,
ataxia-telangiectasia, and Fanconi anemia) that are characterized
by hypersensitivity to DNA-damaging agents, such as ionizing
radiation
BRCA1 and BRCA2, which are mutated in familial breast cancers,
are involved in DNA repair

Karyotypic Changes in Tumors

Tumor cells may develop a variety of nonrandom
chromosomal abnormalities that contribute to
malignancy; these include balanced translocations,
deletions, and cytogenetic manifestations of gene
amplification
Balanced translocations contribute to carcinogenesis by
overexpression of oncogenes or generation of novel
fusion proteins with altered signaling capacity
Deletions frequently affect tumor suppressor genes,
whereas gene amplification increases the expression of
oncogenes
Tumor suppressor genes and DNA repair genes may
also be silenced by epigenetic changes, which involve
reversible, heritable changes in gene expression that
occur, not by mutation, but by methylation of the
promoter