SHIPi Enhances Autologous and Allogeneic Hematolymphoid Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) is a highly effective procedure enabling long-term survival for patients with hematologic malignancy or heritable defects. Although there has been a dramatic increase in the success rate of HSCT over the last two decades, HSCT can result in serious, sometime untreatable, disease due to toxic conditioning regimens, graft vs. host disease and required use of mismatched bone marrow in some cases. Studies utilizing germline knockout mice have discovered several candidate genes that could be targeted pharmacologically to create a more favorable environment for transplant success. SHIP1 deficiency permits improved engraftment of hematopoietic stem-progenitor cells (HS-PC) and produces a suppressive microenvironment ideal for incoming grafts. The recent development of small molecule SHIP1 inhibitors has opened a different therapeutic approach to creating transient SHIP1-deficiency. Here we show that SHIP1 inhibition (SHIPi) can mobilize functional HS-PC, accelerate hematologic recovery, and enhance donor HS-PC engraftment in both allogeneic and autologous transplant settings. We also observed the expansion of key cell populations known to suppress host-reactive cells formed during engraftment. Therefore, SHIPi represents a non-toxic, new therapeutic that has significant potential to improve the success and safety of therapies that utilize HSCT.