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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INTRODUCTION
The development of cancer is a step-wise accumulation
of genetic and epigenetic alterations including
chromosome rearrangements that, in most cases,
involve proto-oncogenes. Production of multiple copies
of particular gene or gene amplification (amp) is
one of the basic mechanisms that lead to over expression
of oncogenes [1]. It is a frequent event in solid tumors
but is rather rare in malignant hemopathies [1,2].
Genes with affinity to genomic over representation in
myeloid malignancy such as acute myeloid leukemia
(AML) and myelodysplastic syndromes (MDS) and
others, are c-MYC, MLL and more rarely RUNX1 and
ETV6 [3-7].
The MLL gene (located in region 11q23) is a transcriptional
factor that normally regulates expression of
mir-196b, a hematopoietic microRNA located within
the HoxA cluster [8]. The MLL over expression resulting
from amp of MLL (amp MLL) leads to over expression
of the functionally related HOX genes, provoking
an increased cell proliferative capacity and survival,
as well as a partial block in differentiation [4,8]. The
presence of additional MLL copies in the genotype of
the patients with MDS increases the transformation
potential of the affected cell clones, which results in
evolution to AML [4].
The MYC proteins play a well defined role as the
components of signal transduction pathways promoting
both cell proliferation and apoptosis [9,10]. The
c-MYC gene (located in region 8q24) is frequently
over expressed in human cancers, but the downstream
events contributing to the tumor genesis remain incompletely
understudied [3,10]. The next step of the
disease progression would be if the amp of c-MYC
(amp c-MYC) and amp MLL is accompanied by proven
over expressions of corresponding genes [4,10].
Total or partial trisomy is an unbalanced karyotypic
anomaly which is more frequently a secondary
event in the development of a neoplasia [11]. Trisomy
8 (+8) occurs in 10 to 20% of the cases with myeloid
malignances in contrast to the more rare but non random
aberration, trisomy 11 (+11) [12-14]. According
to the United Kingdom Medical Research Council
(MRC) criteria and World Health Organization
classification-based prognostic scoring system, the
prognostic value of these anomalies for achieving a
complete remission in AML and for transformation in
MDS is intermediate, but if +8 or +11 is attendant with
over representation or/and amplification of c-MYC
and MLL genes, the prognosis assessment would be
worse [4,10,15-16]. The final step in the malignant cell
clone development that predicts resistance to therapy
is karyotype complexity [15]. The 8q24 (c-MYC) and
11q23 (MLL) gains were observed in about 40% of the
cases with AML and complex karyotype [17]. The objective
of this study was to investigate the correlation
between cytogenetically defined +8 or +11 in karyotypes
at a different level of clonal cell development
with molecular genetically proved amp c-MYC or amp
MLL genes.
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