An Effective Model of HL-60 Differentiation

We present an effective model All-Trans Retinoic Acid (ATRA)-induced differentiation of HL-60 cells. The model describes a key architectural feature of ATRA-induced differentiation, positive feedback between an ATRA-inducible signalsome complex involving many proteins including Vav1, a guanine nucleotide exchange factor, and the activation of the mitogen activated protein kinase (MAPK) cascade. The model, which was developed by integrating logical rules with kinetic modeling, was significantly smaller than previous models. However, despite its simplicity, it captured key features of ATRA induced differentiation of HL-60 cells. We identified an ensemble of effective model parameters using measurements taken from ATRAinduced HL-60 cells. Using these parameters, model analysis predicted that MAPK activation was bistable as a function of ATRA exposure. Conformational experiments supported ATRAinduced bistability. These findings, combined with other literature evidence, suggest that positive feedback is central to a diversity of cell fate programs.