title: Targeting PI3Kδ and PI3Kγ signalling disrupts human AML survival and bone marrow stromal cell mediated protection.
abstract: Phosphoinositide-3-kinase (PI3K) is an enzyme group, known to regulate key survival pathways in acute myeloid leukaemia (AML). It generates phosphatidylinositol-3,4,5-triphosphate, which provides a membrane docking site for protein kinaseB activation. PI3K catalytic p110 subunits are divided into 4 isoforms; α,β,δ and γ. The PI3Kδ isoform is always expressed in AML cells, whereas the frequency of PI3Kγ expression is highly variable. The functions of these individual catalytic enzymes have not been fully resolved in AML, therefore using the PI3K p110δ and p110γ-targeted inhibitor IPI-145 (duvelisib) and specific p110δ and p110γ shRNA, we analysed the role of these two p110 subunits in human AML blast survival. The results show that PI3Kδ and PI3Kγ inhibition with IPI-145 has anti-proliferative activity in primary AML cells by inhibiting the activity of AKT and MAPK. Pre-treatment of AML cells with IPI-145 inhibits both adhesion and migration of AML blasts to bone marrow stromal cells. Using shRNA targeted to the individual isoforms we demonstrated that p110δ-knockdown had a more significant anti-proliferative effect on AML cells, whereas targeting p110γ-knockdown significantly inhibited AML migration. The results demonstrate that targeting both PI3Kδ and PI3Kγ to inhibit AML-BMSC interactions provides a biologic rationale for the pre-clinical evaluation of IPI-145 in AML.
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.
authors.forename: Genevra
authors.initials: G
authors.lastname: Pillinger
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.
authors.forename: Niamh V
authors.initials: NV
authors.lastname: Loughran
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Piddock
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.
authors.forename: Manar S
authors.initials: MS
authors.lastname: Shafat
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.
authors.forename: Lyubov
authors.initials: L
authors.lastname: Zaitseva
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.
authors.forename: Amina
authors.initials: A
authors.lastname: Abdul-Aziz
authors.affiliation: Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, NR4 7UY, United Kingdom.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Lawes
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.|Department of Haematology, Norfolk and Norwich University Hospitals NHS Trust, Norwich, NR4 7UY, United Kingdom.
authors.forename: Kristian M
authors.initials: KM
authors.lastname: Bowles
authors.affiliation: Department of Molecular Haematology, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich, NR4 7TJ, United Kingdom.
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Rushworth
mesh_terms: D001854:Bone Marrow Cells / Q000166:cytology*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D058534:Class I Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D016172:DNA Fingerprinting; D015973:Gene Expression Regulation, Leukemic; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D015470:Leukemia, Myeloid, Acute / Q000235:genetics / Q000378:metabolism*; D059630:Mesenchymal Stem Cells / Q000166:cytology*; D010766:Phosphorylation; D011687:Purines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D016896:Treatment Outcome
chemical_list: D007546:Isoquinolines; D011687:Purines; D034741:RNA, Small Interfering; C586691:duvelisib; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; C486018:PIK3CD protein, human; C546760:PIK3CG protein, human
keywords: AML; PI3Kγ; PI3Kδ; bone marrow stromal cells; duvelisib