Differentiation of Acute Promyelocytic Leukemia Cells by All-trans Retinoic Acid and A Cyclin-Dependent Kinase Inhibitor Involves Dissociation of a CDK4/C/EBP ε Complex

Tsolkas G, Komninou D, Papanik

Abstract

Cell differentiation involves exiting the cell cycle and activating gene programs that are responsible for differentiation. The cyclin-dependent CDK4 kinase regulates the cell cycle at the G1/S stage and is an important molecule that contributes to tumorigenic mechanisms in nearly all neoplasms. CDK4 links the cell cycle to mitogenic/anti-mitogenic signals with unknown mechanisms cooperating with Cyclin D1. The cellular "decision" for differentiation or continuous proliferation occurs predominantly in the G1/S phase with mechanisms dependent on the type of cells with CDK4 kinase having a key role. We have recently demonstrated that the combination of sub-pharmaceutical doses of retinoic acid (ATPA) and CDK1/CDK2 inhibitors in acute promyelocytic leukemia (APL) cells induces degradation of CDK4 protein by simultaneously differentiating cells into granulocytes. In this paper we report that in proliferating NB4 cells, C/EBPε and CDK4 interact whereas treatment of the cells with a CDK1/CDK2 inhibitor and sub-pharmacological levels of all-trans retinoic acid leads to dissociation of the two proteins concomitantly with granulocytic differentiation of the leukemic cells. Our data suggest that CDK4/C/EBPε complexes may contribute to APL cell proliferation and that their dissociation may be required for differentiation.