Esculetin Downregulates the Expression of AML1-ETO and C-Kit in Kasumi-1 Cell Line by Decreasing Half-Life of mRNA

الملخص EN

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.