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miR-155 expression is associated with chemoimmunotherapy outcome and is modulated by Bruton’s tyrosine kinase inhibition with Ibrutinib

Leukemia volume 29, pages 1210–1213 (2015)Cite this article

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Chronic lymphocytic leukemia (CLL) is an incurable disease identified most commonly in elderly patients. Interphase cytogenetics, IGHV status and ZAP70 protein expression/methylation have been used to risk stratify patients relative to likelihood of disease progression or treatment assignment when CLL becomes symptomatic.(reviewed in 1) microRNAs (miRs) are short non-coding RNAs that posttranscriptionally regulate mRNAs for degradation or translational block. Recently, miR expression profiling in CLL has been used to identify miR signatures that predict disease progression and explain disease biology. miR expression profiling in CLL has been able to identify miRs that correlate with shorter time of diagnosis to treatment, such as miR-155 (high), miR-29c (low) and miR-181a (high).2 In patients treated with frontline therapy fludarabine, miR profiling identified variable expression of miR-148a, miR-21 and miR-222 at pretreatment could be predicative of response.3 One of the most studied miRs, miR-155 and its host gene BIC, have been previously indicated to be overexpressed in CLL and has been found to be leukemogeneic when overexpressed under a B-cell-specific promoter in mice.4, 5 To further elucidate the clinical impact of baseline miR-155 expression, we examined clinical outcome of previously untreated patients treated with chemoimmunotherapy. A previous study using the CLL MEC1 cell line demonstrated targeting miR-155 lead to inhibition of proliferation.6 miR-155 is critical for B-cell development and can be enhanced by antigen receptor stimulation.7, 8 miR-155 has been found to be upregulated in B-cell receptor (BCR) stimulated B cells. Also, increased miR-155 expression has been linked to a BCR-activated phenotype characterized by unmutated IGVH and high ZAP70 expression.2, 7, 8, 9 Given the relationship of between active BCR signaling and miR-155 expression, we examined the influence of the BCR-targeted therapy, Bruton’s tyrosine kinase inhibitor, ibrutinib, on expression of this onco-miR in vivo among patients at different time points during their treatment.

Given the potential oncogenic role of miR-155 and contribution of its overexpression to shortened PFS and OS with chemoimmunotherapy in CLL, we next sought to determine if this could be therapeutically targeted. The BCR-activated phenotype is known to be closely associated with patients with poor prognostic factors, such as high ZAP70 expression and unmutated IGHV status.9 Associations between miR-155 expression, ZAP70 expression and IGHV mutational status and BCR activation have been made in recent literature.2, 12 It has been observed that CLL patients with high miR-155 are generally more responsive to BCR ligation, showing a greater amount of anti-μ-induced calcium flux, compared with patients with low miR-155.12 The distinct relationship between BCR activation and miR-155 led to the hypothesis that BCR-targeted therapies could potentially modulate miR-155 expression. Ibrutinib, an irreversible inhibitor, which binds cysteine 481 of Bruton’s tyrosine kinase (BTK), has been previously shown to decrease pro-survival signaling, such as AKT, ERK and NFκB.13 BTK has been found to be an integral kinase in the BCR pathway and important to the development and survival of leukemic B cells in the Eμ-TCL1 mouse model and also in in vitro analysis of primary CLL cells.14 Ibrutinib has also been shown to be highly effective as a treatment in relapsed or refractory CLL.15 It was found that patients with unmutated IGHV disease, who are likely to have greater dependence on BCR stimulation, were found to clear their lymphocytosis earlier and meet traditional criteria for response.15 Although multiple BCR-targeted genes were shown to be decreased by ibrutinib, the influence on miR-155 expression was not examined.

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References

  1. Hallek M . Chronic lymphocytic leukemia: 2013 update on diagnosis, risk stratification and treatment. Am J Hematol 2013; 88: 803–816.

    Article  CAS  PubMed  Google Scholar 

  2. Calin GA, Ferracin M, Cimmino A, Di Leva G, Shimizu M, Wojcik SE et al. A microRNA signature associated with prognosis and progression in chronic lymphocytic leukemia. N Engl J Med 2005; 353: 1793–1801.

    Article  CAS  PubMed  Google Scholar 

  3. Ferracin M, Zagatti B, Rizzotto L, Cavazzini F, Veronese A, Ciccone M et al. MicroRNAs involvement in fludarabine refractory chronic lymphocytic leukemia. Mol Cancer 2010; 9: 123.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Eis PS, Tam W, Sun L, Chadburn A, Li Z, Gomez MF et al. Accumulation of miR-155 and BIC RNA in human B cell lymphomas. PNAS 2005; 102: 3627–3632.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Costinean S, Zanesi N, Pekarsky Y, Tilli E, Volinia S, Heerema N et al. Pre-B cell proliferation and lymphoblastic leukemia high-grade lymphoma in Eμ-miR155 transgenic mice. PNAS 2006; 103: 7024–7029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Zhang Y, Roccaro AM, Rombaoa C, Flores L, Obad S, Fernandes SM et al. LNA-mediated anti-miR-155 silencing in low-grade B cell lymphomas. Blood 2012; 120: 1678–1686.

    Article  CAS  PubMed  Google Scholar 

  7. Elton TS, Selemon H, Elton SM, Parinandi NL . Regulation of MIR155 host gene in physiological and pathological processes. Gene 2013; 532: 1–12.

    Article  CAS  PubMed  Google Scholar 

  8. Mraz M, Kipps TJ . MicroRNAs and B cell receptor signaling in chronic lymphocytic leukemia. Leuk Lymphoma 2013; 54: 1836–1839.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wiestner A, Rosenwald A, Barry TS, Wright G, Davis RE, Henrickson SE et al. ZAP-70 expression identifies a chronic lymphocytic leukemia subtype with unmutated immunoglobulin genes, inferior clinical outcome, and distinct gene expression profile. Blood 2003; 101: 4944–4951.

    Article  CAS  PubMed  Google Scholar 

  10. Byrd JC, Peterson BL, Morrison VA, Park K, Jacobson R, Hoke E et al. Randomized phase 2 study of fludarabine with concurrent versus sequential treatment with rituximab in symptomatic, untreated patients with B-cell chronic lymphocytic leukemia: results from Cancer and Leukemia Group B 9712 (CALGB 9712). Blood 2003; 101: 6–14.

    Article  CAS  PubMed  Google Scholar 

  11. Lin TS, Donohue KA, Byrd JC, Lucas MS, Hoke EE, Bengtson EM et al. Consolidation therapy with subcutaneous alemtuzumab after fludarabine and rituximab induction therapy for previously untreated chronic lymphocytic leukemia: Final Analysis of CALGB 10101. J Clin Oncol 2010; 28: 4500–4506.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Cui B, Chen L, Zhang S, Mraz M, Fecteau JF, Yu J et al. MicroRNA-155 influences B-cell receptor signaling and associates with aggressive disease in chronic lymphocytic leukemia. Blood 2014; 124: 546–554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Herman SE, Gordon AL, Hertlein E, Ramanunni A, Zhang X, Jaglowski S et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood 2011; 117: 6287–6296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Woyach JA, Bojnik E, Ruppert AS, Stefanovski MR, Goettl VM, Smucker KA et al. Bruton's tyrosine kinase (BTK) function is important to the development and expansion of chronic lymphocytic leukemia (CLL). Blood 2014; 123: 1207–1213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Byrd JC, Furman RR, Coutre SE, Flinn IW, Burger JA, Blum KA et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013; 369: 32–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jaglowski SM, jones JA, flynn JM, andritsos LA, maddocks KJ, blum KA et al. A phase ib/ii study evaluating activity and tolerability of btk inhibitor PCI-32765 and of atumumab in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (cll/sll) and related diseases. J clin oncol 2012; 30 (suppl; abstract 6508).

  17. Maddocks K, Flynn JM, Andritsos LA, Awan F, Woyach JA, Grever MR et al. A phase 2 study of the BTK inhibitor ibrutinib in genetic risk-stratifed relapsed and refractory patients with chronic lymphocytic leukemia (CLL)/ small lymphocytic lymphoma (SLL). EHA 2014: (abstract S1342).

  18. Woyach JA, Smucker K, Smith LL, Lozanski A, Zhong Y, Ruppert AS et al. Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood 2014; 123: 1810–1817.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Woyach JA, Ruppert As, Lozanski G, Lozanski A, Heerema N A, Weiqiang Z et al. Association of disease progression on ibrutinib therapy with the acquisition of resistance mutations: a single-center experience of 267 patients. J Clin Oncol 2014; 32: 5s.

    Article  Google Scholar 

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Acknowledgements

The authors wish to thank the families who provided samples for this work. This work was supported by Specialized Center of Research from the Leukemia and Lymphoma Society, P50-CA140158, P01 CA95426 and R01 CA177292 from the National Cancer Institute, The D Warren Brown Foundation, Four Winds Foundation, The Sullivan Chronic Lymphocytic Leukemia Research Fund, Mr and Mrs Michael Thomas, Mr and Mrs Al Lipkin and The Harry T Mangurian Foundation.

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Authors and Affiliations

  1. Biomedical Sciences Graduate Program, College of Medicine, The Ohio State University, Columbus, OH, USA

    D Guinn

  2. Division of Hematology, Department of Internal Medicine and Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA

    D Guinn, A S Ruppert, K Maddocks, S Jaglowski, A Gordon, G Marcucci, E Hertlein, J Woyach, A J Johnson & J C Byrd

  3. Oncology Research and Development, GlaxoSmithKline, Philadelphia, PA, USA

    T S Lin

  4. Department of Medicine, University of Chicago, Chicago, IL, USA

    R Larson

  5. Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH, USA

    A J Johnson & J C Byrd

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Guinn, D., Ruppert, A., Maddocks, K. et al. miR-155 expression is associated with chemoimmunotherapy outcome and is modulated by Bruton’s tyrosine kinase inhibition with Ibrutinib. Leukemia 29, 1210–1213 (2015). https://doi.org/10.1038/leu.2014.344

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