ИСТИНА

The t(8;21)(q22;q22) rearrangement represents the most common chromosomal translocation in acute myeloid leukemia (AML) and results in appearance of a transcript encoding for the fusion protein RUNX1-RUNX1T1 which is considered to be an attractive target for treating t(8;21) leukemia. However, expression of this gene alone is insufficient to cause transformation, and thus the potential of such therapy remains unclear whether the RUNX1-RUNX1T1-driven activation of key genes, participating in tumor progression, may be sufficiently reversed by downregulation of RUNX1-RUNX1T1. We used the RNA-interference (RNAi) approach for elucidation of the functional consequences of RUNX1-RUNX1T1 suppression in the t(8;21)-positive AML Kasumi-1 cell line. We observed significant decrease of KIT expression, inhibited growth and enhanced apoptosis of the leukemic cells. We obtained the model t(8;21) cell line with suppressed RUNX1-RUNX1T1 able to proliferate for many passages, and performed a genome-wide microarray-based screening of gene expression. We showed that the supression of RUNX1-RUNX1T1 can lead to up- and downregulation of signaling pathways enhancing cell survival and proliferation. We provide evidence that the inhibition of this oncoprotein or gene alone may be insufficient to treat the leukemic cells. We identified that the protein ERK2, one of the key regulators responsible for cell proliferation, can mediate activation of 23/29 (79%) of these pathways and, thus, may be regarded as the key player in establishing the anti-RUNX1-RUNX1T1 therapy resistant phenotype. We speculate that supplementing therapy with targeting ERK2 and/or other members of RUNX1-RUNX1T1 regulatory network may be advantageous in developing treatments of t(8;21)- positive leukemia.