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

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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