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Abstract
Acquisition of multi-drug resistance (MDR) is a major hindrance towards the successful treatment of cancers. Over expression of a range of ATP-dependent efflux pumps, particularly ABCB1 is a widely reported mechanism of cancer cell MDR. Approximately 30% acute myeloid leukemia (AML) patients demonstrate ABCB1 over expression. Several mechanisms for up regulation of ABCB1 have been proposed. Our aim was to investigate the role of genomic amplification of the chromosome 7 region with regard to its influence on ABCB1 over expression in AML cell line. For this, we developed Doxorubicin (Dox) resistant leukemic cell line from K562 cells, demonstrating MDR phenotype. The chromosomal changes associated with the acquisition of MDR were characterized by array- based comparative genomic hybridization (aCGH) with the parental K562 cell line as the reference genome. Significant genomic gains in the chromosomal region corresponding to 7q11.21-7q22.1 were observed in Dox selected cell line. Moreover, the amplicon contains the ABCB1 gene locus at 7q21.1 with a copy number gain of >4. ABCB1 mRNA was found to be up-regulated by54-fold. Our results demonstrate that the development of MDR in K562/Dox is underlined by a genomic amplification of the chromosome 7 region harboring the ABCB1 gene.
Highlights
Acute myeloid leukemia (AML) is a complex and heterogeneous disease with poor clinical outcome, especially in the elderly who constitute the majority of acute myeloid leukemia (AML) patients [1]
Our results demonstrate that the development of multi-drug resistance (MDR) in K562/Dox is underlined by a genomic amplification of the chromosome 7 region harboring the ATP binding cassette sub family B member1 (ABCB1) gene
Dox sensitivity in K562 and Dox resistant K562 cell line: Dox-resistant cell lineK562/Dox was derived from K562 parental cells by culturing the cells in gradually incremental doses of Dox (10nM -200nM) followed by clonal selection
Summary
Acute myeloid leukemia (AML) is a complex and heterogeneous disease with poor clinical outcome, especially in the elderly who constitute the majority of AML patients [1]. The treatment strategies for selected subtypes of AML has recently started to change [2]. For the majority of the AML patients, conventional chemotherapy remains the frontline therapeutic choice. In younger AML patients, 70-80% achieve complete remission (CR) but most of them eventually relapse and overall survival (OS) in this group is only 40-50% at 5 years [3]. The primary reason for the failure of AML therapy is drug resistance. Multidrug resistance (MDR), which is the simultaneous acquisition of resistance to different chemotherapeutic agents, is a daunting clinical challenge in AML.
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