SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell Transplantation

Sandra Fernandes, Robert Brooks, Matthew Gumbleton, Mi Young Park, Christopher M. Russo, Kyle T. Howard, John D. Chisholm, William G. Kerr

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)205-213
Number of pages9
JournalEBioMedicine
Volume2
Issue number3
DOIs
StatePublished - Mar 1 2015

Keywords

  • 3AC
  • Allogeneic BMT
  • Autologous BMT
  • MMP-9
  • NK cells
  • SDF-1
  • SHIP1
  • SHIPi
  • Stem cell mobilization

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Fernandes, S., Brooks, R., Gumbleton, M., Park, M. Y., Russo, C. M., Howard, K. T., Chisholm, J. D., & Kerr, W. G. (2015). SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell Transplantation. EBioMedicine, 2(3), 205-213. https://doi.org/10.1016/j.ebiom.2015.02.004