Leukemogenic AML1-ETO fusion protein upregulates expression of connexin 43: The role in AML1-ETO-induced growth arrest in leukemic cells<FNR></FNR><FN>Xi Li and Ya-Bei Xu contributed equally to this work. </FN>.

AML1-ETO, a fusion protein generated by the chromosomal translocation t(8;21), is frequently associated with acute myeloid leukemia (AML). In addition to blocking differentiation, AML1-ETO is also shown to induce growth arrest in AML cells, which is unfavorable for leukemogenesis harboring the t(8;21) translocation. However, its precise mechanism is still unclear. Here we provide the first demonstration that the conditional expression of AML1-ETO by the ecdysone-inducible system dramatically increases the expression of connexin 43 (CX43), together with growth arrest at G₁ phase in leukemic U937 cells. We also show that the CX43 induction inhibits the proliferation of U937 cells at G₁ phase, while the suppression of CX43 expression by small interfering RNA (siRNA) effectively overcomes the growth-inhibitory effect of AML1-ETO in leukemic cells. Furthermore, either AML1-ETO or CX43 induction elevates cell-cycle negative regulator P27^kip1 protein by inhibiting its degradation, which is antagonized by siRNA against CX43. Taken together, our data indicate that CX43 plays a role in AML1-ETO-induced growth arrest possibly through the accumulation of P27^kip1 protein. The potential mutation or/and epigenetic alterations of CX43 and its related gene(s) deserve to be explored in AML1-ETO-positive AML patients. J. Cell. Physiol. 208: 594–601, 2006. © 2006 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]