SHIP1 inhibition increases immunoregulatory capacity and triggers apoptosis of hematopoietic cancer cells.
Genetic studies revealed that SHIP1 limits blood cell production and immune regulatory cell numbers in vivo. We postulated that molecular targeting of SHIP1 might enhance blood cell production and increase immunoregulatory capacity. In this study, we report the identification of a chemical inhibitor of SHIP1, 3 alpha-aminocholestane (3AC). Treatment with 3AC significantly expands the myeloid immunoregulatory cell compartment and impairs the ability of peripheral lymphoid tissues to prime allogeneic T cell responses. In addition, 3AC treatment profoundly increases granulocyte production without triggering the myeloid-associated lung consolidation observed in SHIP1(-/-) mice. Moreover, 3AC also enhances RBC, neutrophil, and platelet recovery in myelosuppressed hosts. Intriguingly, we also find that chemical inhibition of SHIP1 triggers apoptosis of blood cancer cells. Thus, SHIP1 inhibitors represent a novel class of small molecules that have the potential to enhance allogeneic transplantation, boost blood cell production, and improve the treatment of hematologic malignancies.
Brooks
Robert
R
Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.
Fuhler
Gwenny M
GM
Iyer
Sonia
S
Smith
Michelle J
MJ
Park
Mi-Young
MY
Paraiso
Kim H T
KH
Engelman
Robert W
RW
Kerr
William G
WG
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002469:Cell Separation; D002776:Cholestanes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005434:Flow Cytometry; D019337:Hematologic Neoplasms / Q000276:immunology*; D006801:Humans; D000072181:Inositol Polyphosphate 5-Phosphatases; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000187:drug effects / Q000276:immunology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000276:immunology*
C548903:3alpha-aminocholestane; D002776:Cholestanes; D004791:Enzyme Inhibitors; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606430:INPP5D protein, human; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases