References
Burger JA, Tedeschi A, Barr PM, Robak T, Owen C, Ghia P, et al. Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia. N Engl J Med. 2015;373:2425–37.
Woyach JA, Furman RR, Liu TM, Ozer HG, Zapatka M, Ruppert AS, et al. Resistance mechanisms for the Bruton’s tyrosine kinase inhibitor ibrutinib. N Engl J Med. 2014;370:2286–94.
Brunner C, Muller B, Wirth T. Bruton’s tyrosine kinase is involved in innate and adaptive immunity. Histol Histopathol. 2005;20:945–55.
Kenny EF, Quinn SR, Doyle SL, Vink PM, van Eenennaam H, O'Neill LA. Bruton’s tyrosine kinase mediates the synergistic signalling between TLR9 and the B cell receptor by regulating calcium and calmodulin. PLoS ONE. 2013;8:e74103.
Ntoufa S, Vardi A, Papakonstantinou N, Anagnostopoulos A, Aleporou-Marinou V, Belessi C, et al. Distinct innate immunity pathways to activation and tolerance in subgroups of chronic lymphocytic leukemia with distinct immunoglobulin receptors. Mol Med. 2012;18:1281–91.
Kurosaki T, Tsukada S. BLNK: connecting Syk and Btk to calcium signals. Immunity. 2000;12:1–5.
Ntoufa S, Papakonstantinou N, Apollonio B, Gounari M, Galigalidou C, Fonte E, et al. B cell anergy modulated by TLR1/2 and the miR-17 approximately 92 cluster underlies the indolent clinical course of chronic lymphocytic leukemia stereotyped subset #4. J Immunol. 2016;196:4410–7.
Herman SE, Mustafa RZ, Gyamfi JA, Pittaluga S, Chang S, Chang B, et al. Ibrutinib inhibits BCR and NF-kappaB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood. 2014;123:3286–95.
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;123:1810–7.
Ponader S, Chen SS, Buggy JJ, Balakrishnan K, Gandhi V, Wierda WG, et al. The Bruton tyrosine kinase inhibitor PCI-32765 thwarts chronic lymphocytic leukemia cell survival and tissue homing in vitro and in vivo. Blood. 2012;119:1182–9.
Khan WN, Alt FW, Gerstein RM, Malynn BA, Larsson I, Rathbun G, et al. Defective B cell development and function in Btk-deficient mice. Immunity. 1995;3:283–99.
Zorn CN, Keck S, Hendriks RW, Leitges M, Freudenberg MA, Huber M. Bruton’s tyrosine kinase is dispensable for the Toll-like receptor-mediated activation of mast cells. Cell Signal. 2009;21:79–86.
Jayappa KD, Portell CA, Gordon VL, Capaldo BJ, Bekiranov S, Axelrod MJ, et al. Microenvironmental agonists generate de novo phenotypic resistance to combined ibrutinib plus venetoclax in CLL and MCL. Blood Adv. 2017;1:933–46.
Sagiv-Barfi I, Kohrt HE, Burckhardt L, Czerwinski DK, Levy R. Ibrutinib enhances the antitumor immune response induced by intratumoral injection of a TLR9 ligand in mouse lymphoma. Blood. 2015;125:2079–86.
Furman RR, Cheng S, Lu P, Setty M, Perez AR, Guo A, et al. Ibrutinib resistance in chronic lymphocytic leukemia. N Engl J Med. 2014;370:2352–4.
Acknowledgements
This work was supported in part by the framework of action “IKY Fellowships of excellence for postgraduate studies in Greece - SIEMENS program”; GCH-CLL project funded by ERA-NET TRANSCAN-2 Joint Transnational Call for Proposals 2014 (JTC 2014) and project #179 NOVEL funded by ERA-NET TRANSCAN-2 JTC 2016, by the European Commission/DG Research and Innovation; ODYSSEUS Programme, implemented under the “Action for the Strategic Development on the Research and Technological Sector”, funded by the Operational Programme “Competitiveness, Entrepreneurship and Innovation” (NSRF 2014–2020) and co-financed by Greece and the European Union (European Regional Development Fund); AIRC Investigator grants #20246 and #16777, and Special Program AIRC 5 per mille #21198, Associazione Italiana per la Ricerca sul Cancro AIRC, Milano, Italy; Progetti di Rilevante Interesse Nazionale (PRIN) 2015ZMRFEA, MIUR, Roma, Italy. Maria Gounari and Theodoros Moysiadis are recipients of Marie Sklodowska-Curie individual fellowships (Grant Agreement Numbers: 796491 and 702714, respectively), funded by the European Union’s Horizon 2020 research and innovation programme. Kostas Stamatopoulos and Paolo Ghia received urestricted research funding to this project by Janssen Pharmaceuticals.
Author information
Authors and Affiliations
Contributions
MG and SN designed the research, performed the study, and wrote the manuscript; MG, MGV, KK, NP, AA, EF, PR, and AN assisted in experiments; TM performed statistical analysis; LS, AX, MC, AT, and NS provided patient samples and clinical information; MM, KS, and PG designed and supervised the research and wrote the manuscript.
Corresponding author
Ethics declarations
Conflict of interest
KS received honoraria from AbbVie, Gilead Science, Janssen and reseach funding from AbbVie, Gilead, Janssen. PG received honoraria from AbbVie, Acerta, BeiGene, Gilead, Janssen, Sunesis and reseach funding from AbbVie, Gilead, Janssen, Novartis. The remaining authors declare that they have no conflict of interest.
Additional information
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Gounari, M., Ntoufa, S., Gerousi, M. et al. Dichotomous Toll-like receptor responses in chronic lymphocytic leukemia patients under ibrutinib treatment. Leukemia 33, 1030–1051 (2019). https://doi.org/10.1038/s41375-018-0335-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41375-018-0335-2
- Springer Nature Limited