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Chronic lymphocytic leukemia

Ibrutinib downregulates a subset of miRNA leading to upregulation of tumor suppressors and inhibition of cell proliferation in chronic lymphocytic leukemia

Leukemia volume 31, pages 340–349 (2017)Cite this article

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Abstract

The lymph node (LN) is the site of chronic lymphocytic leukemia (CLL) cell activation and proliferation. Aberrant microRNA (miRNA) expression has been shown to have a role in CLL pathogenesis; however, a comparison of miRNA expression between CLL cells in the LN and the peripheral blood (PB) has previously not been reported. On the basis of the analysis of 17 paired LN and PB samples from CLL patients, we identify a panel of miRNAs that are increased in LN CLL cells correlating with an activation phenotype. When evaluated in CLL cells from 38 patients pre and post treatment with ibrutinib, a subset of these miRNAs (miR-22, miR-34a, miR-146b and miR-181b) was significantly decreased in response to ibrutinib. A concomitant increase in putative miRNA target transcripts (ARID1B, ARID2, ATM, CYLD, FOXP1, HDAC1, IBTK, PTEN and SMAD4) was also observed. Functional studies confirmed targets of ibrutinib-responsive miRNAs to include messenger RNA transcripts of multiple tumor suppressors. Knockdown of endogenous miR-34a and miR146b resulted in increased transcription of tumor suppressors and inhibition of cell proliferation. These findings demonstrate that ibrutinib downregulates the expression of a subset of miRNAs related to B-cell activation leading to increased expression of miRNA targets including tumor suppressors and a reduction in cell proliferation.

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Acknowledgements

This work was supported by the National Institutes of Health Division of Intramural Research, NIH Clinical Center, and National Heart, Lung and Blood Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services. We thank Dr Masanori Daibata (Kochi University Medical School, Kochi, Japan) for use of the SP53 cell line.

Author contributions

LMS, WW, SEMH, NKA, ZZ, OE, HAA, AW and KRC designed the study. LMS, WW, SEMH, NSS, EB, MC-C and VA performed the experiments. LMS, WW, VA and KRC analyzed the data and wrote the manuscript. SMS and LMS performed the statistical analyses. MF and CS provided clinical care and patient samples. AW, SEMH, ZZ and HAA assisted in editing the manuscript.

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Authors and Affiliations

  1. Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD, USA

    L M Saleh, W Wang, V Anastas, E Barber, M Corrigan-Cummins, Z Zhao & K R Calvo

  2. Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, USA

    S E M Herman, N S Saba, M Farooqui, C Sun & A Wiestner

  3. Greenwood Genetic Center, Greenwood, SC and School of Nursing, Clemson University, Clemson, SC, USA

    S M Sarasua

  4. Clinical Pathology Department, Faculty of Medicine, Mansoura University, Mansoura, Egypt

    L M Saleh, N K Abousamra, O Elbaz & H A Abdelghaffar

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  1. L M Saleh
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Correspondence to K R Calvo.

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AW has received research funding from Pharmacyclics. The remaining authors declare no conflict of interest.

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Saleh, L., Wang, W., Herman, S. et al. Ibrutinib downregulates a subset of miRNA leading to upregulation of tumor suppressors and inhibition of cell proliferation in chronic lymphocytic leukemia. Leukemia 31, 340–349 (2017). https://doi.org/10.1038/leu.2016.181

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