Rap1A, Rap1B, and β-Adrenergic Signaling in Autologous HCT: A Randomized Controlled Trial of Propranolol

Abstract

Successful hematopoietic cell transplantation (HCT) depends on rapid engraftment of the progenitor and stem cells that will reestablish hematopoiesis. Rap1A and Rap1B are two closely related small GTPases that may affect platelet and neutrophil engraftment during HCT through their roles in cell adhesion and migration. β-adrenergic signaling may regulate the participation of Rap1A and Rap1B in engraftment through their inhibition or activation. We conducted a correlative study of a randomized controlled trial evaluating the effects of the nonselective β-antagonist propranolol on expression and prenylation of Rap1A and Rap1B during neutrophil and platelet engraftment in 25 individuals receiving an autologous HCT for multiple myeloma. Propranolol was administered for 1 week prior to and 4 weeks following HCT. Blood was collected 7 days (baseline) and 2 days (Day -2) before HCT, and 28 days after HCT (Day +28). Circulating polymorphonuclear cells (PMNC) were isolated and analyzed via immunoblotting to determine levels of prenylated and total Rap1A versus Rap1B. Twelve participants were randomized to the intervention and 13 to the control. Rap1A expression significantly correlated with Rap1B expression. Rap1B expression significantly correlated with slower platelet engraftment; however, this association was not observed in the propranolol-treated group. There were no significant associations between neutrophil engraftment and Rap1A or Rap1B expression. Post hoc exploratory analyses did not reveal an association between social health variables and Rap1A or Rap1B expression. This study identifies a greater regulatory role for Rap1B than Rap1A in platelet engraftment and suggests a possible role for β-adrenergic signaling in modulating Rap1B function during HCT.

Keywords: Engraftment; Hematopoiesis; Propranolol; Rap1; β-adrenergic.