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Chronic Lymphocytic Leukemia

Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation

Leukemia volume 29, pages 115–125 (2015)Cite this article

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Abstract

Chronic lymphocytic leukemia (CLL) is characterized by accumulation of clonal B cells arrested in G0/G1 stages that coexist, in different proportions, with proliferative B cells. Understanding the crosstalk between the proliferative subsets and their milieu could provide clues on CLL biology. We previously identified one of these subpopulations in the peripheral blood from unmutated patients that appears to be a hallmark of a progressive disease. Aiming to characterize the molecular mechanism underlying this proliferative behavior, we performed gene expression analysis comparing the global mRNA and microRNA expression of this leukemic subpopulation, and compared it with their quiescent counterparts. Our results suggest that proliferation of this fraction depend on microRNA-22 overexpression that induces phosphatase and tensin homolog downregulation and phosphoinositide 3-kinase (PI3K)/AKT pathway activation. Transfection experiments demonstrated that miR-22 overexpression in CLL B cells switches on PI3K/AKT, leading to downregulation of p27−Kip1 and overexpression of Survivin and Ki-67 proteins. We also demonstrated that this pathway could be triggered by microenvironment signals like CD40 ligand/interleukin-4 and, more importantly, that this regulatory loop is also present in lymph nodes from progressive unmutated patients. Altogether, these results underline the key role of PI3K/AKT pathway in the generation of the CLL proliferative pool and provide additional rationale for the usage of PI3K inhibitors.

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Acknowledgements

This work was supported by grants from ANII: Fondo Clemente Estable (FCE-7273) and Fondo Maria Viña (FMV-7323). This work was partially funded by Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET), Argentina, FOCEM (MERCOSUR Structural Convergence Fund), COF 03/11 and CYTED Program. We thank Dr Alfonso Cayota for his help in the microRNA technologies, the Cell Biology Unit of the Institut Pasteur de Montevideo for their technical assistance in cell sorting analysis and Mrs Ivana Faccini for her helpful assistance with the manuscript correction. We also thank the patients with CLL for their cooperation and help in providing invaluable blood samples for this work.

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Authors and Affiliations

  1. Recombinant Protein Unit, Institut Pasteur de Montevideo, Montevideo, Uruguay

    F Palacios, C Abreu, D Prieto, P Morande & P Oppezzo

  2. Immunobiology Department, School of Medicine, Universidad de la República, Montevideo, Uruguay

    F Palacios & P Oppezzo

  3. Department of Neurodevelopmental Biology, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, Uruguay

    S Ruiz

  4. Bioinformatics Unit, Institut Pasteur de Montevideo, Montevideo, Uruguay

    T Fernández-Calero & H Naya

  5. Molecular Biology Unit, Institut Pasteur de Montevideo, Montevideo, Uruguay

    G Libisch & C Robello

  6. Service of Hematology and Bone Marrow Transplantation, Hospital Maciel, Montevideo, Uruguay

    A I Landoni, R Gabus & G Dighiero

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  1. F Palacios
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Correspondence to P Oppezzo.

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Author Contributions

FP, CA, DP, PM and SR performed experiments and collected CLL samples; TF-C, HN, GL and CR performed microarrays and statistical analysis; ANL, GD and RG performed clinical activities and data collection of CLL patients; PO and GD contributed to scientific design and revised the paper; PO and FP designed research, coordinated the study and data analysis and wrote the paper.

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Palacios, F., Abreu, C., Prieto, D. et al. Activation of the PI3K/AKT pathway by microRNA-22 results in CLL B-cell proliferation. Leukemia 29, 115–125 (2015). https://doi.org/10.1038/leu.2014.158

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