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PI3Kδ inhibition elicits anti-leukemic effects through Bim-dependent apoptosis

PI3Kδ inhibition elicits anti-leukemic effects through Bim-dependent apoptosis
PI3Kδ inhibition elicits anti-leukemic effects through Bim-dependent apoptosis
PI3Kδ plays pivotal roles in the maintenance, proliferation and survival of malignant B-lymphocytes. Although not curative, PI3Kδ inhibitors (PI3Kδi) demonstrate impressive clinical efficacy and, alongside other signaling inhibitors, are revolutionizing the treatment of hematological malignancies. However, only limited in vivo data are available regarding their mechanism of action. With the rising number of novel treatments, the challenge is to identify combinations that deliver curative regimes. A deeper understanding of the molecular mechanism is required to guide these selections. Currently, immunomodulation, inhibition of B-cell receptor signaling, chemokine/cytokine signaling and apoptosis represent potential therapeutic mechanisms for PI3Kδi. Here we characterize the molecular mechanisms responsible for PI3Kδi-induced apoptosis in an in vivo model of chronic lymphocytic leukemia (CLL). In vitro, PI3Kδi-induced substantive apoptosis and disrupted microenvironment-derived signaling in murine (Eμ-Tcl1) and human (CLL) leukemia cells. Furthermore, PI3Kδi imparted significant therapeutic responses in Eμ-Tcl1-bearing animals and enhanced anti-CD20 monoclonal antibody therapy. Responses correlated with upregulation of the pro-apoptotic BH3-only protein Bim. Accordingly, Bim−/− Eμ-Tcl1 Tg leukemias demonstrated resistance to PI3Kδi-induced apoptosis were refractory to PI3Kδi in vivo and failed to display combination efficacy with anti-CD20 monoclonal antibody therapy. Therefore, Bim-dependent apoptosis represents a key in vivo therapeutic mechanism for PI3Kδi, both alone and in combination therapy regimes.
0887-6924
1423–1433
Carter, Matthew
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Cox, Kerry
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Blakemore, Stuart
1b8f7beb-1d31-4182-b78e-066994e706b2
Turaj, Anna
fbbc48ea-28cf-4db7-ae4a-c16ce7b3857a
Oldham, Robert
f43d1416-0b93-4dfd-a504-2850cb43e87e
Dahal, Lekh
1e993a7a-b007-4187-82ea-e28dd3920b66
Tannheimer, Stacey
38d5302d-abae-4760-8b9d-7533321d8fb3
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c
Carter, Matthew
3baac102-d80c-42ba-ab4d-ad339a48169e
Cox, Kerry
7305c27e-9cdc-4e37-b994-ac55d7d1dfd2
Blakemore, Stuart
1b8f7beb-1d31-4182-b78e-066994e706b2
Turaj, Anna
fbbc48ea-28cf-4db7-ae4a-c16ce7b3857a
Oldham, Robert
f43d1416-0b93-4dfd-a504-2850cb43e87e
Dahal, Lekh
1e993a7a-b007-4187-82ea-e28dd3920b66
Tannheimer, Stacey
38d5302d-abae-4760-8b9d-7533321d8fb3
Forconi, Francesco
ce9ed873-58cf-4876-bf3a-9ba1d163edc8
Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Cragg, Mark
ec97f80e-f3c8-49b7-a960-20dff648b78c

Carter, Matthew, Cox, Kerry, Blakemore, Stuart, Turaj, Anna, Oldham, Robert, Dahal, Lekh, Tannheimer, Stacey, Forconi, Francesco, Packham, Graham and Cragg, Mark (2017) PI3Kδ inhibition elicits anti-leukemic effects through Bim-dependent apoptosis. Leukemia, 31 (6), 1423–1433. (doi:10.1038/leu.2016.333).

Record type: Article

Abstract

PI3Kδ plays pivotal roles in the maintenance, proliferation and survival of malignant B-lymphocytes. Although not curative, PI3Kδ inhibitors (PI3Kδi) demonstrate impressive clinical efficacy and, alongside other signaling inhibitors, are revolutionizing the treatment of hematological malignancies. However, only limited in vivo data are available regarding their mechanism of action. With the rising number of novel treatments, the challenge is to identify combinations that deliver curative regimes. A deeper understanding of the molecular mechanism is required to guide these selections. Currently, immunomodulation, inhibition of B-cell receptor signaling, chemokine/cytokine signaling and apoptosis represent potential therapeutic mechanisms for PI3Kδi. Here we characterize the molecular mechanisms responsible for PI3Kδi-induced apoptosis in an in vivo model of chronic lymphocytic leukemia (CLL). In vitro, PI3Kδi-induced substantive apoptosis and disrupted microenvironment-derived signaling in murine (Eμ-Tcl1) and human (CLL) leukemia cells. Furthermore, PI3Kδi imparted significant therapeutic responses in Eμ-Tcl1-bearing animals and enhanced anti-CD20 monoclonal antibody therapy. Responses correlated with upregulation of the pro-apoptotic BH3-only protein Bim. Accordingly, Bim−/− Eμ-Tcl1 Tg leukemias demonstrated resistance to PI3Kδi-induced apoptosis were refractory to PI3Kδi in vivo and failed to display combination efficacy with anti-CD20 monoclonal antibody therapy. Therefore, Bim-dependent apoptosis represents a key in vivo therapeutic mechanism for PI3Kδi, both alone and in combination therapy regimes.

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More information

Accepted/In Press date: 21 October 2016
e-pub ahead of print date: 15 November 2016
Published date: 2017
Organisations: Cancer Sciences

Identifiers

Local EPrints ID: 402173
URI: http://eprints.soton.ac.uk/id/eprint/402173
ISSN: 0887-6924
PURE UUID: 55581d2a-08a6-4993-98bc-0b23d707428f
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691
ORCID for Mark Cragg: ORCID iD orcid.org/0000-0003-2077-089X

Catalogue record

Date deposited: 11 Nov 2016 09:16
Last modified: 17 Jun 2020 04:01

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Contributors

Author: Matthew Carter
Author: Kerry Cox
Author: Stuart Blakemore
Author: Anna Turaj
Author: Robert Oldham
Author: Lekh Dahal
Author: Stacey Tannheimer
Author: Graham Packham ORCID iD
Author: Mark Cragg ORCID iD

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