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CHRONIC LYMPHOCYTIC LEUKEMIA

Idelalisib activates AKT via increased recruitment of PI3Kδ/PI3Kβ to BCR signalosome while reducing PDK1 in post-therapy CLL cells

Leukemia volume 36, pages 1806–1817 (2022)Cite this article

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Abstract

Idelalisib targets PI3Kδ in the BCR pathway generating only a partial response in CLL patients, indicating that the leukemic cells may have evolved escape signals. Indeed, we detected increased activation of AKT accompanied by upregulation of MYC/BCL2 in post-therapy CLL cells from patients treated with idelalisib/ofatumumab. To unravel the mechanism of increased AKT-activation, we studied the impact of idelalisib on a CLL-derived cell line, MEC1, as a model. After an initial inhibition, AKT-activation level was restored in idelalisib-treated MEC1 cells in a time-dependent manner. As BCAP (B-cell adaptor for PI3K) and CD19 recruit PI3Kδ to activate AKT upon BCR-stimulation, we examined if idelalisib-treatment altered PI3Kδ-recruitment. Immunoprecipitation of BCAP/CD19 from idelalisib-treated MEC1 cells showed increased recruitment of PI3Kδ in association with PI3Kβ, but not PI3Kα or PI3Kγ and that, targeting both PI3Kδ with PI3Kβ inhibited AKT-reactivation. We detected similar, patient-specific recruitment pattern of PI3K-isoforms by BCAP/CD19 in post-idelalisib CLL cells with increased AKT-activation. Interestingly, a stronger inhibitory effect of idelalisib on P-AKT (T308) than S473 was discernible in idelalisib-treated cells despite increased recruitment of PI3Kδ/PI3Kβ and accumulation of phosphatidylinositol-3,4,5-triphosphate; which could be attributed to reduced PDK1 activity. Thus, administration of isoform-specific inhibitors may prove more effective strategy for treating CLL patients.

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Fig. 1: Post-idelalisib CLL cells express aberrantly activated signal mediators.
Fig. 2: Post-idelalisib CLL cells show increased activation of AKT.
Fig. 3: Impact of idelalisib-based treatment on AKT activation status in long-term follow-up CLL patients and its downstream targets, MYC and BCL2.
Fig. 4: Idelalisib treatment induces increased recruitment of PI3Kδ and PI3Kβ to the BCR signalosome.
Fig. 5: Idelalisib therapy promotes increased recruitment of PI3Kδ and PI3Kβ to the BCR signalosome in post-therapy primary CLL cells.
Fig. 6: Measurement of PIP3 levels in idelalisib treated MEC1 cells.
Fig. 7: Post-idelalisib CLL cells showed increased accumulation of PIP3.
Fig. 8: Idelalisib reduces PDK1 protein level.

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Acknowledgements

We thank all the CLL patients who participated in this study. This work was supported partly by a research fund from the National Cancer Institute (CA170006) and a Presbyterian Health Foundation (C5126601) Bridge grant to AKG. We also acknowledge the support received from the NCI Cancer Center Support Grant (P30 CA225520). In addition, this study was also supported in part by the Oklahoma Tobacco Settlement Endowment Trust awarded to the University of Oklahoma//Stephenson Cancer Center. JRB was supported by NIH R01 CA 213442.

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  1. These authors contributed equally: Hasan Mahmud, Guru P. Maiti.

Authors and Affiliations

  1. Stephenson Cancer Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Murali K. Mamidi, Hasan Mahmud, Guru P. Maiti, Sara K. Vesely, Jennifer Holter-Chakrabarty & Asish K. Ghosh

  2. Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Mariana T. Mendez & Asish K. Ghosh

  3. Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

    Stacey M. Fernandes & Jennifer R. Brown

  4. Hudson College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA

    Sara K. Vesely

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Contributions

MKM, HM, GPM, MTM and SF performed experiments and collected data. MKM created the figures and table. SKV and JHC edited the manuscript. JRB provided clinical samples with relevant information, and edited the manuscript. AKG conceived and supervised the project, designed the research, analyzed data, and wrote the manuscript. All authors read and approved the final manuscript.

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Correspondence to Asish K. Ghosh.

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Competing interests

JRB has served as a consultant for Abbvie, Acerta, Astra-Zeneca, Beigene, Catapult, Dynamo Therapeutics, Eli Lilly, Juno/Celgene, Kite, MEI Pharma, Nextcea, Novartis, Octapharma, Pfizer, Rigel, Sunesis, TG Therapeutics, Verastem; received honoraria from Janssen; received research funding from Gilead, Loxo, Sun and Verastem; and served on data safety monitoring committees for Invectys. All other authors declare that there are no competing financial interests.

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Mamidi, M.K., Mahmud, H., Maiti, G.P. et al. Idelalisib activates AKT via increased recruitment of PI3Kδ/PI3Kβ to BCR signalosome while reducing PDK1 in post-therapy CLL cells. Leukemia 36, 1806–1817 (2022). https://doi.org/10.1038/s41375-022-01595-0

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