SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell Transplantation

a r t i c l e i n f o Keywords: SHIP1 3AC Allogeneic BMT Autologous BMT Stem cell mobilization SDF-1 MMP-9 NK cells SHIPi 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, sometimes untreatable disease due to toxic conditioning regimens and Graft-versus-Host-Disease. 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-PCs) and produces an immunosuppressive microenvironment ideal for incoming allogeneic grafts. The recent development of small molecule SHIP1 inhibitors has opened a different therapeutic approach by creating transient SHIP1-deficiency. Here we show that SHIP1 inhibition (SHIPi) mobilizes functional HS-PC, accelerates hematologic recovery, and enhances 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 autologous and allogeneic HSCT. Hematopoietic stem cell transplantation (HSCT) has historically been successful in treating patients with cancer, autoimmune disease (multiple sclerosis), and genetic disorders (thalassemia, sickle cell disease) (Li and Sykes, 2012). Prior to HSCT, an intense conditioning regimen is essential to reduce host tumor burden and/or auto-reactive lymphocytes. The pro-inflammatory state triggered by pre-transplant conditioning also enhances T and NK cell killing of residual tumor cells particularly in the allogeneic setting (Paulos et al., 2007). However, this same inflammatory milieu can promote donor or host T-cell reactions that culminate in Graft-versus-Host-Disease (GvHD) or in graft rejection (Shlomchik, 2007, Ferrara et al., 2009). Many patients who require HSCT do not have an appropriate human leukocyte antigen (HLA) matched donor available. Additionally, HLA mismatch can be beneficial for cancer patients as an HLA mismatch results in increased NK cell activity (Davies et al., 2002, Ruggeri et al., 2002). Therefore, a major goal for optimizing HSCT is to enhance the engraftment of HLA mismatched grafts, while preventing, or reducing the undesired side effects triggered by the graft, the intense preconditioning regimens, or both. SHIP1 and SHIP2 are two SH2-domain containing inositol 5′ phos-phatases that oppose the …