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Blood, 15 March 2002, Vol. 99, No. 6, pp. 1909-1912
PERSPECTIVE
Genetic pathways in therapy-related myelodysplasia and acute
myeloid leukemia
Jens Pedersen-Bjergaard,
Mette K. Andersen,
Debes H. Christiansen, and
Claus Nerlov
From the Cytogenetic Laboratory, Section of
Hematology/Oncology, Department of Clinical Genetics, the Juliane Marie
Center and the Laboratory of Gene Therapy Research, the Laboratory
Center, Rigshospitalet, University Hospital of Copenhagen, Denmark.
 |
Abstract |
Therapy-related acute myeloid leukemia (t-AML) in most cases
develops after chemotherapy of other malignancies and shows
characteristic chromosome aberrations. Two general types of t-AML have
previously been identified. One type is observed after therapy with
alkylating agents and characteristically presents as therapy-related
myelodysplasia with deletions or loss of the long arms of chromosomes 5 and 7 or loss of the whole chromosomes. The other type is observed
after therapy with topoisomerase II inhibitors and characteristically presents as overt t-AML with recurrent balanced chromosome aberrations. Recent research suggests that these 2 general types of t-AML can now be
subdivided into at least 8 genetic pathways with a different etiology
and different biologic characteristics.
(Blood. 2002;99:1909-1912)
| |
Introduction |
The genetic events leading to malignant
transformation in most human tumors remain more or less concealed. A
sequence of specific gene mutations has been identified in a few
malignancies such as hereditary colon cancer and has in this disease
been related to a stepwise transformation of normal epithelium to
dysplastic cells, papillomas and, finally, localized or disseminated
cancer.1
Recent research indicates that myelodysplasia (MDS), often
progressing to acute myeloid leukemia (AML), may represent a similar although more complicated model for leukemic transformation. Most cases
of MDS and AML arise de novo without verified leukemogenic exposures.
However, in a subset of 10% to 20% of the patients, the disease
arises after previous therapy, most often chemotherapy, of other
malignancies. Because the risk of therapy-related MDS (t-MDS) and
therapy-related AML (t-AML) after intensive chemotherapy is often
increased 100 times or more,2 99 of 100 cases of t-MDS and
t-AML observed in this type of patient must be considered as excess
cases directly induced by the cytostatic agents.
Approximately 50% to 60% of patients with MDS and AML de novo present
chromosome abnormalities of unknown etiology,3,4 and in
cases of overt AML there is most often no knowledge about a preleukemic
phase of MDS. However, in t-MDS and t-AML, 85% to 90% of the patients
show chromosome aberrations generally of the same types as observed in
MDS and AML de novo,5-7 and the cytogenetic changes can be
related to previous exposure to different chemically well-defined
cytostatic agents with a known mechanism of action. In cases of overt
t-AML a preleukemic phase of t-MDS, if present, is most often diagnosed
at an early stage of the disease because of a regular follow-up with
laboratory investigations of patients treated intensively with chemotherapy.
| |
Previous classification of t-MDS and t-AML |
For 2 decades, deletions or loss of 5q and 7q or monosomy of these
2 chromosomes have been closely associated with previous therapy with
alkylating agents and with presentation of the disease as
t-MDS.5-7 The abnormalities of chromosomes 5 and 7 in
t-MDS and t-AML have been classified together, and the abnormalities of
chromosome 7, which are the most commonly observed, have for this
reason sometimes been considered as the primary
changes.7
Many years later, another general type of t-AML was observed.
Abnormalities of the long arm of chromosome 11 were initially observed
in cases of overt t-AML after therapy with the
epipodophyllotoxins.8-10 Subsequently, a variety of
balanced translocations involving chromosome bands 11q23 or 21q22 in
t-MDS and t-AML were shown to be significantly related to previous
therapy with the whole group of topoisomerase II
inhibitors.11,12 Based on this experience, 2 main groups of t-MDS and t-AML were defined,13 and their different
genetic pathways were discussed.7 Much new information has
now been obtained for both general types of t-MDS and t-AML, and for
this reason we wish to propose a revised model for the genetic pathways of these diseases.
| |
Revised model for cytogenetic and genetic pathways in t-MDS
and t-AML |
Pathway I in the revised model (Figure
1) includes cases with deletions or loss
of 7q or monosomy 7 but with normal chromosome 5. The
abnormalities of chromosome 7 are the most commonly observed in t-MDS
and t-AML following therapy with alkylating agents,5-7 but
they are sometimes observed in only a subclone of cells or as
evolutionary events during progression of the disease.14 For this reason, other genetic abnormalities may be the important events in this pathway. Cases of t-MDS and t-AML with deletions or loss
of 7q or monosomy 7 in many cases present additional chromosome aberrations, sometimes a balanced t(3;21)7 characteristic
of t-MDS. Although the prognosis of patients belonging to pathway I is
generally poor, some cases of t-MDS with monosomy 7 as the sole
abnormality, only a modest cytopenia, and without an excess of blasts
in the bone marrow may survive even for years on supportive therapy
only.15 Mutations of the RAS
genes16,17 and methylation of the of the p15
gene promotor (D.H.C., J.P.-B., manuscript submitted) have been
observed frequently in this pathway, but they probably do not represent
primary genetic abnormalities in leukemic transformation. Mutations of
p53 are not very common.18,19
Pathway II includes cases of t-MDS and t-AML with deletions or
loss of 5q or monosomy 5. These abnormalities have recently in most
cases been unveiled by multicolor fluorescence in situ hybridization as
unbalanced translocations to 5q.20,21 Defects of
the long arm of chromosome 5 is the second most common cytogenetic abnormality of t-MDS and t-AML after therapy with alkylating agents. Abnormalities of chromosome 5 were in our series of patients always observed in all abnormal mitoses at diagnosis and were never seen as
evolutionary events or in only a subclone.14 For this
reason they were considered to represent more important changes in
leukemogenesis than the defects of chromosome 7. Patients with
abnormalities of chromosome 5 characteristically present many
additional chromosome aberrations, including unidentified marker
chromosomes, and sometimes deletions or loss of 7q or monosomy 7 also
are observed. Mutations of the p53 gene are very common in
this pathway. In 2 studies of 98 cases of t-MDS and t-AML, 20 of 26 patients with deletion or loss of 5q presented p53
mutations, versus 7 of 72 patients with normal chromosome
518,19 (P < .001,  2 test).
The marker chromosomes in some cases have been identified as
extensively deleted chromosome 5 or 720,21 and in other cases as derivative chromosomes with duplication or amplification of
chromosome band 11q23, including the unrearranged MLL
gene.22 Patients in pathway II have an extremely poor
prognosis, particularly if p53 is mutated with loss of
heterozygosity of the gene.19
Pathway III comprises patients with balanced translocations to
chromosome band 11q23 characteristically presenting as overt t-AML.
These translocations are often observed without additional chromosome
abnormalities and are the most frequently observed aberrations in t-AML
following therapy with the epipodophyllotoxins.8-10 Many
patients observed with these abnormalities are children.9 Patients with balanced translocations to 11q23 often obtain a complete
remission following intensive antileukemic therapy, but the prognosis,
even in children, is poor due to relapse of t-AML.23 In
this pathway the MLL gene at 11q23 is chimerically
rearranged with one of its many partner genes. An interesting example
is the MLL-CBP fusion of the t(11;16) predominantly observed
in t-AML.24 Mutations of p53 are infrequent in
this and in the following pathways.19,25
Pathway IV in the former model was dominated by adult patients with
overt t-AML and t(8;21).11,12 Subsequently, cases of t-AML
with inv(16) also were observed related to therapy with topoisomerase
II inhibitors,26-28 often an anthracycline. These patients
present chimeric rearrangements of the core binding factor genes
AML1(CBFA) at 21q22 and CBFB at 16q22, and they
often have additional chromosome aberrations. Patients in this pathway
show the best results following intensive antileukemic chemotherapy, and they often become long-term survivors.
Pathway V comprises cases of therapy-related acute promyelocytic
leukemia with t(15;17) and chimeric rearrangement between the
PML and the RARA genes. Such cases were first
reported recurrently in Chinese patients treated with bimolane, a
razoxane-related topoisomerase II inhibitor, for
psoriasis.29 Subsequently, similar cases were observed
after treatment with other topoisomerase II inhibitors, including
anthracyclines, mitoxantrone,28,30-32 and radiotherapy
only.33 Patients in this pathway often respond favorably to intensive antileukemic chemotherapy plus retinoic acid.
Pathway VI comprises more recently observed and rather rare cases of
t-MDS and t-AML with different balanced translocations to chromosome
band 11p15 and chimeric rearrangement between the NUP98 gene
and its various partner genes.34-38 Almost half of the patients with these abnormalities developed leukemia after
administration of topoisomerase II inhibitors, most often etoposide or
anthracyclines or a combination of these drugs.
An important, still unsolved question is the extent to which each
individual balanced chromosome aberration in pathways III to VI is
associated with a specific topoisomerase II inhibitor. In a review of
the literature of 442 cases of t-MDS and t-AML with balanced chromosome
aberrations,33 it was shown that balanced translocations
to 11q23, previous therapy with epipodophyllotoxins, and younger age
were all significantly interrelated. When taking age into account in a
multivariate analysis, there was no longer a significant association
between previous therapy with epipodophyllotoxins and t-AML with
translocations to 11q23. Thus, age and perhaps other factors such as
race could explain the associations observed between specific drugs and
specific cytogenetic subgroups of t-MDS and t-AML.
Pathway VII includes the subgroup of 10% to 15% of patients with
t-MDS or t-AML and a normal karyotype, a subgroup well known for many
years.5-7 As in AML de novo,39 it has been
shown by multicolor fluorescence in situ hybridization that
patients with t-MDS or t-AML and a normal karyotype only rarely present
new cryptic cytogenetic rearrangements undetected by conventional G-banding.21 Unlike most patients with therapy-related
leukemia and unbalanced chromosome aberrations, cases with a normal
karyotype for unknown reasons predominantly present as overt
t-AML.7 They have not been shown to be associated with any
specific type of previous therapy, and they often respond to intensive
antileukemic chemotherapy.7 Recently, we observed internal
tandem duplications of the FLT3 or of the MLL
gene in 4 of 6 patients with overt t-AML and a normal karyotype,
whereas only 1 of another 76 patients with t-MDS or t-AML presented an
MLL duplication.40 Both types of duplication
were apparently not related to any specific type of previous therapy.
Internal tandem duplications of the FLT3 and the
MLL genes have previously been demonstrated mainly in cases
of AML de novo with a normal karyotype,41-45 and the
MLL duplications have been suggested to develop by
endogenous recombinations at Alu repeats. In conclusion, patients with
internal tandem duplications of FLT3 and MLL and
perhaps also other patients in this pathway with a normal karyotype
could represent sporadic and incidental cases of AML de novo unrelated
to previous mutagenic exposures.
Pathway VIII includes patients with various chromosome aberrations
uncharacteristic of t-MDS and t-AML. Some of these may likewise
represent incidental cases of MDS and AML de novo; others may later
turn out as recurrent but more rare cytogenetic abnormalities of t-MDS
and t-AML.
| |
Mouse models of human MDS and AML |
Classification of t-MDS and t-AML in different genetic pathways
may seem premature because major parts of leukemogenesis are still
poorly understood. For instance, the specific genetic abnormalities directly cooperating with or predisposing to deletions or loss of the
long arms of chromosomes 5 and 7 are still completely unknown. As far
as the recurrent balanced chromosome aberrations in pathways III to V
are concerned, recently developed mouse models support that their
chimeric fusion genes are directly involved in
leukemogenesis.46-56 It has been possible by various
techniques to introduce these genes with appropriate promoters in mouse
bone marrow precursors, and in many instances this resulted in the
development of leukemia in a high percentage of the animals. Although
the technique used has varied from study to study, and although caution
must be taken in comparing these highly experimental models with human
leukemia,57 at least 3 important observations have
been made.
First, leukemias in mice develop after a latent period that sometimes
is rather long, indicating that additional genetic events are required
for leukemic transformation. Second, the phenotype of the leukemias
observed in mice is sometimes very similar to its human counterpart.
Thus, introduction of the PML-RARA fusion gene in mouse bone
marrow progenitors resulted in the development of retinoic
acid-sensitive promyelocytic leukemia,46-49 and
introduction of 2 different MLL fusion genes resulted in the
development of leukemias with monocytic differentiation or
myelomonocytic leukemias.50,51 Finally, the potential to
induce leukemias in mice seems to vary between the different chimeric
genes. Thus, the AML1-MDS1-EVI1 fusion gene, primarily
observed in the t(3;21) at blastic transformation of chronic myeloid
leukemia and subsequently in t-MDS, often induced leukemia,52 whereas another 2 rearrangements of core
binding factor genes, the AML1-ETO from the
t(8;21)53,54 and the CBFB-MYH11 from the
inv(16),55,56 so far have been shown only to induce defective and dysplastic hematopoiesis or impaired neutrophil maturation. The transforming potential of these transcripts has been
suggested as more restricted,54 and additional exposure to
a single sublethal dose of N-ethyl-N-nitrosourea was in one of these
studies required for subsequent development of overt leukemia.56 The persistence of the AML1-ETO
fusion transcript in bone marrow cells from most patients in long-term
remission after intensive chemotherapy or even bone marrow
transplantation of AML with t(8;21)58-60 further supports
that the transcript, even if detected in vivo in human bone marrow
cells, is not firmly associated with the development of overt leukemia.
| |
Conclusion |
The proposed model of genetic pathways in t-MDS and t-AML relates
3 types of etiology alkylating agents, topoisomerase II inhibitors,
and spontaneous endogenous recombinations unrelated to exogenous
mutagenic exposuresto a complicated framework of cytogenetic and
genetic abnormalities and clinical characteristics of these diseases.
The diversity of cytogenetic and genetic abnormalities of t-MDS and
t-AML is remarkable. Whereas most of the recurrent chromosome
aberrations now must be considered as identified, many invisible
genetic changes still remain to be discovered. Such new abnormalities
could result in a further revision of the model. So far, methylation of
the p15 promotor is the only abnormality observed in a high
percentage of patients with t-MDS and t-AML and in their de novo
counterparts. New techniques such as the microarray equipment for
studies of gene expression may facilitate detection of
additional and more general genetic abnormalities of MDS and AML.
| |
Footnotes |
Submitted August 6, 2001; accepted November 1, 2001.
Supported by grants from the Danish Cancer Society, HS Forskningspulje
1997, and Anders Hasselbalch's Foundation.
© 2002 by the American Society of Hematology
Reprints: Jens Pedersen-Bjergaard, Cytogenetic Laboratory,
Section 4052, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen Ø,
Denmark.
| |
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Abstract
Introduction