PI3K p110δ inactivation antagonizes chronic lymphocytic leukemia and reverses T cell immune suppression

Targeted therapy with small molecules directed at essential survival pathways in leukemia represents a major advance, including the phosphatidylinositol-3'-kinase (PI3K) p110δ inhibitor idelalisib. Here, we found that genetic inactivation of p110δ (p110δD910A/D910A) in the Eμ-TCL1 murine chroni...

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Bibliographic Details
Published in:The Journal of clinical investigation 2019-01, Vol.129 (1), p.122-136
Main Authors: Dong, Shuai, Harrington, Bonnie K, Hu, Eileen Y, Greene, Joseph T, Lehman, Amy M, Tran, Minh, Wasmuth, Ronni L, Long, Meixiao, Muthusamy, Natarajan, Brown, Jennifer R, Johnson, Amy J, Byrd, John C
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Acute myeloid leukemia
Amino Acid Substitution
Animals
Biomedical research
Cancer
CD4 antigen
CD8 antigen
CD8-Positive T-Lymphocytes - immunology
CD8-Positive T-Lymphocytes - pathology
Cell adhesion & migration
Cell migration
Chemokines
Chronic lymphocytic leukemia
Class I Phosphatidylinositol 3-Kinases - genetics
Class I Phosphatidylinositol 3-Kinases - immunology
Colitis
Cytokines
Disease resistance
Enzyme Activation - genetics
Enzyme Activation - immunology
Enzyme inhibitors
Homeostasis
Immune clearance
Immune system
Immune Tolerance
Immunomodulation
Inflammatory bowel disease
Kinases
Leukemia
Leukemia, Lymphoid - genetics
Leukemia, Lymphoid - immunology
Leukemia, Lymphoid - pathology
Leukemia, Lymphoid - therapy
Lymphatic leukemia
Lymphocytes
Lymphocytes B
Lymphocytes T
Medical prognosis
Mice
Mice, Transgenic
Microbiota
Mutation, Missense
Myeloid leukemia
Neoplasms, Experimental - genetics
Neoplasms, Experimental - immunology
Neoplasms, Experimental - pathology
Neoplasms, Experimental - therapy
Rectum
T-Lymphocytes, Regulatory - immunology
T-Lymphocytes, Regulatory - pathology
Tumors
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Summary:Targeted therapy with small molecules directed at essential survival pathways in leukemia represents a major advance, including the phosphatidylinositol-3'-kinase (PI3K) p110δ inhibitor idelalisib. Here, we found that genetic inactivation of p110δ (p110δD910A/D910A) in the Eμ-TCL1 murine chronic lymphocytic leukemia (CLL) model impaired B cell receptor signaling and B cell migration, and significantly delayed leukemia pathogenesis. Regardless of TCL1 expression, p110δ inactivation led to rectal prolapse in mice resembling autoimmune colitis in patients receiving idelalisib. Moreover, we showed that p110δ inactivation in the microenvironment protected against CLL and acute myeloid leukemia. After receiving higher numbers of TCL1 leukemia cells, half of p110δD910A/D910A mice spontaneously recovered from high disease burden and resisted leukemia rechallenge. Despite disease resistance, p110δD910A/D910A mice exhibited compromised CD4+ and CD8+ T cell response, and depletion of CD4+ or CD8+ T cells restored leukemia. Interestingly, p110δD910A/D910A mice showed significantly impaired Treg expansion that associated with disease clearance. Reconstitution of p110δD910A/D910A mice with p110δWT/WT Tregs reversed leukemia resistance. Our findings suggest that p110δ inhibitors may have direct antileukemic and indirect immune-activating effects, further supporting that p110δ blockade may have a broader immune-modulatory role in types of leukemia that are not sensitive to p110δ inhibition.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI99386