SHIP1 Inhibition Increases Immunoregulatory Capacity and Triggers Apoptosis of Hematopoietic Cancer Cells
Open accessAbstract
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 α-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.
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3AC at 1.25 μM reduces INPP5D activity in primary mouse microglia well below its reported IC50 of 10 μM.
“A recent study reported reduced INPP5D activity in primary mouse microglia treated with 3AC at a concentration (1.25 μM) well below its reported IC50 (10 μM)39,45.”
From INPP5D regulates inflammasome activation in human microglia (2023) · cites this paper as [39]
The Results section, “A high-throughput screening identifies a SHIP1 selective inhibitor” (page unavailable), reports 50% inhibition of recombinant SHIP1 by 3AC at 10 μM, supporting the reported IC50. It does not report reduced INPP5D activity in primary mouse microglia treated at 1.25 μM. (LLM, conf=0.90)
Experimental — accuracy not yet measured3-alpha-Aminocholestane (3AC) is a selective inhibitor of INPP5D.
“Here, we used 3-alpha-Aminocholestane (3AC), a compound previously reported to be a selective inhibitor of INPP5D39, which has been utilized in several studies to reduce INPP5D activity in vivo in mice and in vitro cell culture39–47.”
From INPP5D regulates inflammasome activation in human microglia (2023) · cites this paper as [39]
Cathepsin B signal appears punctate when localized to lysosomes, whereas it becomes diffuse when localized to the cytosol upon LMP.
“Cathepsin B signal appears punctate when localized to the lysosomes, whereas the signal becomes diffuse (and perhaps below the limit of detection by immunostaining) when localized to the cytosol upon LMP44–46.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [44]
The Materials and Methods passages describe Western blotting and flow-cytometry staining, but not cathepsin B localization. Searches for cathepsin B, lysosomal membrane permeabilization, and punctate versus diffuse immunostaining found no passage addressing the claim. (LLM, conf=0.76)
Experimental — accuracy not yet measuredActive cathepsin B can leak into the cytoplasm after lysosomal membrane permeabilization (LMP) in contexts where lysosomal membrane integrity is compromised, such as upon lysosomal deacidification.
“Second, active cathepsin B can leak into the cytoplasm after lysosomal membrane permeabilization (LMP) in contexts where lysosomal membrane integrity is compromised, such as upon lysosomal deacidification44,69.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [44]
The Results section reports apoptosis after SHIP1 inhibition, and Materials and Methods describes assays for apoptosis-related proteins, but neither addresses cathepsin B release or lysosomal membrane permeabilization. Searches for cathepsin B and lysosomal deacidification found no passage in our copy supporting the attributed mechanism; page numbers were not available. (LLM, conf=0.76)
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Coordinate Expansion of Murine Hematopoietic and Mesenchymal Stem Cell Compartments by SHIPi
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Self-citationRole of Inositol Poly-Phosphatases and Their Targets in T Cell Biology
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Self-citationRole of inositol phospholipid signaling in natural killer cell biology
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A small-molecule inhibitor of SHIP1 reverses age- and diet-associated obesity and metabolic syndrome
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Self-citationSYK and ZAP70 kinases in autoimmunity and lymphoid malignancies
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Lineage extrinsic and intrinsic control of immunoregulatory cell numbers by SHIP
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Self-citationEctopic ILT3 controls BCR-dependent activation of Akt in B-cell chronic lymphocytic leukemia
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TLR signaling that induces weak inflammatory response and SHIP1 enhances osteogenic functions
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Self-citationPhosphatidylinositolphosphate phosphatase activities and cancer
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Human Cytomegalovirus Glycoprotein-Initiated Signaling Mediates the Aberrant Activation of Akt
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Analysis of SHIP1 expression and activity in Crohn’s disease patients
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SHIP negatively regulates type II immune responses in mast cells and macrophages
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Regulation of hematopoietic cell signaling by SHIP-1 inositol phosphatase: growth factors and beyond
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Immunosuppressive Signaling Pathways as Targeted Cancer Therapies
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Siglec-8 Signals Through a Non-Canonical Pathway to Cause Human Eosinophil Death In Vitro
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Strategy for Leukemia Treatment Targeting SHP-1,2 and SHIP
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SHIPi Enhances Autologous and Allogeneic Hematopoietic Stem Cell Transplantation
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SHIP1 and its role for innate immune regulation—Novel targets for immunotherapy
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Monitoring Phosphoinositide Fluxes and Effectors During Leukocyte Chemotaxis and Phagocytosis
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Activated eosinophils in early life impair lung development and promote long-term lung damage
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INPP5D/SHIP1 regulates inflammasome activation in human microglia
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- Authors
- Brooks, R., Fuhler, G. M., Iyer, S., Smith, M. J., Park, M.-Y., Paraiso, K. H. T., Engelman, R. W., & Kerr, W. G.
- Affiliations
- SUNY Upstate Medical University (US)
- Moffitt Cancer Center (US)
- Corresponding author
- Brooks, Robert
- Iyer, Sonia
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-04-01
- Volume
- 184
- Issue
- 7
- Pages
- 3582-3589
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC4123216
- OpenAlex
- W2171716580
- Cited by
- 140
- References
- 38
- Citations by year
- 2026: 8 · 2025: 8 · 2024: 6 · 2023: 12 · 2022: 7 · 2021: 10 · 2020: 8 · 2019: 10 · 2018: 11 · 2017: 8 · 2016: 10 · 2015: 7 · 2014: 6 · 2013: 7 · 2012: 11
- FWCI
- 3.99
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- National Institutes of Health (RO1 DK54767, RO1 HL72523)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Blood disorders and treatments
- Keywords
- SHIP1, immunoregulatory cells, myeloid cells, hematopoiesis, allogeneic T cell response, granulopoiesis, hematologic malignancies, apoptosis, allogeneic transplantation, lung consolidation
- MeSH terms
- Inositol Polyphosphate 5-Phosphatases, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Animals, Cell Separation, Cholestanes, Enzyme Inhibitors, Flow Cytometry, Humans, Lymphocyte Culture Test, Mixed, Lymphocyte Activation, Mice, Inbred BALB C, Mice, Inbred C57BL, Phosphoric Monoester Hydrolases, Blotting, Western, Apoptosis, Mice, Knockout, Hematologic Neoplasms, Myeloid Cells, Cell Line, Tumor, Mice
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