Abstract
One of the most frequent genetic aberrations in acute myeloid leukemia (AML) is chromosomal translocation between AML1/RUNX1 on chromosome 21 and ETO gene on chromosome 8 resulting in the expression of chimeric oncogene AML1-ETO. Although patients with t(8;21) translocation have good prognosis, 5-year survival is observed only in 50% of the cases. AML1-ETO translocation is usually accompanied by overexpression of mutant C-Kit, a tyrosine kinase, which contributes to uncontrolled proliferation of premature blood cells leading to relapse and poor prognosis. We illustrate the potential use of esculetin on leukemic cell line, Kasumi-1, bearing t(8;21) translocation and mutated C-Kit gene. Esculetin decreases the expression of AML1-ETO at both protein and transcript level within 24 hours of treatment. Half-life of AML1-ETO mRNA was reduced from 7 hours to 1.5 hours. Similarly half-life of C-Kit mRNA was reduced to 2 hours from 5 hours in esculetin treated cells. Esculetin also perturbed the expression of ectopically expressed AML1-ETO in U937 cells. The decreased expression of AML1-ETO chimeric gene was associated with increased expression of LAT1 and RUNX3 genes, targets of AML1. We envisage that discovery of a drug candidate which could target both these mutated genes would be a considerable breakthrough for future application.
Highlights
The World Health Organization reported 14.1 million new cases and 8.2 million cancer deaths worldwide in 2012
Acute myeloid leukemia patients harbouring the t(8;21) translocation are generally given a good prognosis at the initiation of treatment and absolute remission is achieved in most of the cases
We propose that, under reduced levels of the chimeric protein, which acts as a repressor, the normal RUNX-1 protein is able to activate the expression of its target genes. These results suggested that the effect of esculetin on C-Kit and AML1-ETO transcript is specific and not due to general transcription inhibition and/or degradation of mRNA
Summary
The World Health Organization reported 14.1 million new cases and 8.2 million cancer deaths worldwide in 2012. Over the few years, cancer including leukemia will surpass cardiovascular diseases [1]. Based on the clinical onset and lineage of the transformed immature leukocytes, leukemia can be acute or chronic and myeloid or lymphoid in origin. Acute myeloid leukemia (AML) is a major class of leukemia, accounting for 20% of acute leukemia, wherein role of translocations and mutations in the malignancy of hematopoietic system is well established [2]. These genetic alterations broadly fall in two categories, Class I and Class II
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