Cyclin A1 regulates WT1 expression in acute myeloid leukemia cells

Abstract

Cyclin A1 is a cell cycle protein that is expressed in testes, brain and CD34-positive hematopoietic progenitor cells. Cyclin A1 is overexpressed in a variety of myeloid leukemic cell lines and in myeloid leukemic blasts. Transgenic cyclin A1 overexpressing mice develop acute myeloid leukemia with low frequency. In this study, we looked for putative target genes of cyclin A1 in hematopoietic cells. Microarray analysis of U937 myeloid cells overexpressing cyclin A1 versus conrol cells detected 35 differential expressed genes, 21 induced and 14 repressed ones upon cyclin A1 overexpression. Among the differentially expressed genes WT1 was chosen for further analysis. Repression of WT1 expression was confirmed on the mRNA and protein level. In addition, WT1 expression was higher in bone marrow, liver and ovary of cyclin A1-/- mice. Isoform analysis showed a profound change of the WT1 isoform ratio in U937 cyclin A1-overexpressing versus control cells. Functional analysis revealed an inhibition of colony growth when WT1 isoforms were transfected into U937 cells, which was not affected by the overexpression of cyclin A1. In addition, overexpression of the WT1-/+ isoform induced a G1 cell cycle arrest which was abrogated upon cotransfection with cyclin A1. This study identified WT1 as a repressed target of cyclin A1 and suggests that the suppression of WT1 in cyclin A1-overexpressing leukemias might play a role in the growth and suppression of apoptosis in these leukemic cells.