AMPLIFICATION OF c-MYC AND MLL GENES
AS A MARKER OF CLONAL CELL PROGRESSION
IN PATIENTS WITH MYELOID MALIGNANCY
AND TRISOMY OF CHROMOSOMES 8 OR 11
Angelova S1,*, Jordanova M2, Spassov B1, Shivarov V1, Simeonova M3,
Christov I4, Angelova P3, Alexandrova K5, Stoimenov A1, Nikolova V1,
Dimova I6, Ganeva P1, Tzvetkov N4, Hadjiev E5, Toshkov S1
*Corresponding Author: Svetlana Angelova, Biologist, Laboratory of Cytogenetics and Molecular Biology,
National Specialized Hospital for Active Therapy of Hematological Diseases, 6, «Plovdivsko pole», Sofia, 1756,
Bulgaria; Tel.: +35929701133; Fax : +35929701107; E-mail: sv_angelru@abv.bg
page: 17
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DISCUSSION
The biological mechanism of the oncoproliferative
activity of the +8 cell clones is explained mostly
with the gene dosage effect [20]. Some authors using
microarray techniques observed overexpression
of genes located on chromosome 8 in trisomic cells
[20,21]. Further microarray analysis demonstrated that
+8 MDS was notable for over expression of immune
and inflammatory genes; some of these gene products
also have roles in cellular proliferation and differentiation
in an angiogenesis, whereas apoptotic inhibitors
were down-regulated [22]. Another proposed explanation
of the biological significance of the extra chromosome
8 was based on the observation of increased
copies of the c-MYC gene that plays a central role as a
downstream mediator of the myeloid leukemogenesis
[23]. Furthermore, a comparative genomic hybridization
ratio measurement revealed that a gain of 8q24 is associated with mutation of the p53 tumor suppressor
gene. The association between the gain at an 8q24 and
the p53 mutation might be attributable to transactivation
of the c-MYC gene by the p53 promoter [24].
Amplification mechanisms are not yet clearly understood
[1-2]. Chromosomes have hot fragile sites that
break under specific conditions and may be associated
with chromosomal instability in cancer as breakpoint
sites for translocation, deletion, and amplification [9].
Low-level amp c-MYC was reported in a number of
patients with +8 AML, +8 MDS and chronic myeloid
leukemia (CML) in blast phase [25-27]. Some authors
suggest that c-MYC is not the true target of the amp but
that abundant expression of another gene(s) included
in an 8q24 amplicon is the pathogenetically important
consequence [28].
In most of our overt AML and sAML +8 cases,
the visible developmental effects such as aberrant cell
clone expansion and the occurrence of additional chromosome
deviations are connected with amp c-MYC
that was observed in 12 of 18 (66.7%) patients. Absence
of an amp c-MYC was found predominantly in
the cases with minor +8 cell clones. We suggest that
amp c-MYC is a logical result of the development in
the proliferating +8 cell populations.
The + 11 is the third most common trisomy in de
novo AML, which is more frequently associated with
two different molecular genetic alterations: partial tandem
duplication (PTD) and amp MLL gene [4,29-31].
In most of the cases, the amp 11q23 (with or without
any microscopically visible alterations) is accompanied
by MLL gene over expression, which leads to a
rapid proliferation of the affected clone and to disease
progression [4,31].
Our group of patients with +11 is quite small to
make definitive conclusions. Most of our patients with
+11 cell clone expansion also demonstrated an amp
MLL. This could be explained by the rapid advance of
the developmentally processes in the proliferating +11
cell clones. The significant level of amp MLL (>10%) in
cases which are suspected of gaining 11q23 in complex
karyotype supported our developmental hypotheses.The prognostic value of +8 and +11 is contradictary.
A number of authors defined them as an intermediate,
others as an adverse prognostic factor [11-
13,15]. On the other hand, in most of the publications,
the presence of amp c-MYC and amp MLL correlate
with disease progression and poor risk for patients
with myeloid malignancies [10,14,21].
We speculate that the conflicting results can be
explained with the difference in the proportion of patients
who had amp c-MYC or amp MLL in different
series. The absence of the gene amp can be logically
connected with the early evolutionary stage of the disease
and with the cohort of early diagnosed patients. If
during the investigation, the later diagnosed patients
with amp c-MYC or amp MLL predominate, a worse
prognostic effect may be expected.
All of our AML patients with +8 and amp c-MYC
had a short OS (about 3.7 months) without hematological
remission as well as the patients with +11 and
amp MLL (about 2.4 months). Two of our MDS patients
with expansion of the tri- and tetrasomy 8 cell
clones had amp c-MYC. Both of them demonstrated
a resistance to chemotherapy, disease progression and
transformation to AML. In contrast, two of the five
patients with +8 without amp c-MYC, achieved hematological
remission and one on them is still alive. We
suppose that appearance of +8 and +11 in karyotype
provoke the further developmental events such as amp
c-MYC or amp MLL that leads to therapy resistance.
The earlier patients with +8 and/or +11 are diagnosed,
the higher are their chances not to have amp c-MYC or
amp MLL and not to be resistant to treatment.
According to the results in our comparatively
small patient group, we can assume that amp c-MYC
and amp MLL are natural developmental events, especially
in cases with an aggressive expansion of the
aberrant cell clone and appearance of additional chromosome
anomalies.
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