Ibrutinib induces rapid down-regulation of inflammatory markers and altered transcription of chronic lymphocytic leukaemia-related genes in blood and lymph nodes
Corresponding Author
Marzia Palma
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Department of Haematology, Karolinska University Hospital, Stockholm, Sweden
These authors contributed equally to this work.Correspondence: Marzia Palma, Department of Haematology, Karolinska University Hospital, 171 76 Stockholm, Sweden.
E-mail: [email protected]
Search for more papers by this authorAleksandra Krstic
Centre for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
These authors contributed equally to this work.Search for more papers by this authorLucia Peña Perez
Centre for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorAnna Berglöf
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorStephan Meinke
Centre for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorQing Wang
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorK. Emelie M. Blomberg
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorMasood Kamali-Moghaddam
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Search for more papers by this authorQiujin Shen
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Search for more papers by this authorGeorg Jaremko
Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorJeanette Lundin
Department of Haematology, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorAyla De Paepe
Centre for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorPetter Höglund
Centre for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorEva Kimby
Department of Haematology, Karolinska University Hospital, Stockholm, Sweden
Centre for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorAnders Österborg
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Department of Haematology, Karolinska University Hospital, Stockholm, Sweden
These authors contributed equally to this work.Search for more papers by this authorRobert Månsson
Department of Haematology, Karolinska University Hospital, Stockholm, Sweden
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
These authors contributed equally to this work.Search for more papers by this authorC. I. Edvard Smith
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
These authors contributed equally to this work.Search for more papers by this authorCorresponding Author
Marzia Palma
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Department of Haematology, Karolinska University Hospital, Stockholm, Sweden
These authors contributed equally to this work.Correspondence: Marzia Palma, Department of Haematology, Karolinska University Hospital, 171 76 Stockholm, Sweden.
E-mail: [email protected]
Search for more papers by this authorAleksandra Krstic
Centre for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
These authors contributed equally to this work.Search for more papers by this authorLucia Peña Perez
Centre for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorAnna Berglöf
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorStephan Meinke
Centre for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorQing Wang
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorK. Emelie M. Blomberg
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorMasood Kamali-Moghaddam
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Search for more papers by this authorQiujin Shen
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
Search for more papers by this authorGeorg Jaremko
Department of Pathology and Cytology, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorJeanette Lundin
Department of Haematology, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorAyla De Paepe
Centre for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorPetter Höglund
Centre for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden
Search for more papers by this authorEva Kimby
Department of Haematology, Karolinska University Hospital, Stockholm, Sweden
Centre for Haematology and Regenerative Medicine, Karolinska Institutet, Stockholm, Sweden
Search for more papers by this authorAnders Österborg
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
Department of Haematology, Karolinska University Hospital, Stockholm, Sweden
These authors contributed equally to this work.Search for more papers by this authorRobert Månsson
Department of Haematology, Karolinska University Hospital, Stockholm, Sweden
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
These authors contributed equally to this work.Search for more papers by this authorC. I. Edvard Smith
Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden
These authors contributed equally to this work.Search for more papers by this authorSummary
In chronic lymphocytic leukaemia (CLL) patients, treatment with the Bruton tyrosine kinase inhibitor ibrutinib induces a rapid shift of tumour cells from lymph nodes (LN) to peripheral blood (PB). Here, we characterized in depth the dynamics of ibrutinib-induced inflammatory, transcriptional and cellular changes in different compartments immediately after treatment initiation in seven relapsed/refractory CLL patients. Serial PB and LN samples were taken before start and during the first 29 days of treatment. Changes in plasma inflammation-related biomarkers, CLL cell RNA expression, B-cell activation and migration markers expression, and PB mononuclear cell populations were assessed. A significant reduction of 10 plasma inflammation markers, the majority of which were chemokines and not CLL-derived, was observed within hours, and was paralleled by very early increase of CD19+ circulating cells. At the RNA level, significant and continuous changes in transcription factors and signalling molecules linked to B-cell receptor signalling and CLL biology was observed in both PB and LN CLL cells already after 2 days of treatment. In conclusion, ibrutinib seems to instantly shut off an ongoing inflammatory response and interfere with diverse sensitive pathways in the LN.
Conflict of interest
EK has received honoraria for consultancy (advisory boards) from Janssen and AbbVie. AÖ has received honoraria and grants from Janssen. The other Authors declare no competing financial interests.
Supporting Information
| Filename | Description |
|---|---|
| bjh15516-sup-0001-Supinfo.pdfPDF document, 1.8 MB |
Figure S1. RNA-sequencing samples display high reproducibility and clear separation between normal B- and CLL-cells. Figure S2. Downstream target genes of BCR signaling, NF/kappa B signaling, E2F and MYC display altered expression. Figure S3. Changes in the lymphocyte profile after treatment initiation. Figure S4. Markers analyzed by flow-cytometry not displaying significant changes upon ibrutinib treatment. Figure S5. Major changes occur in the plasmacytoid dendritic cells and monocyte compartment during ibrutinib treatment. Figure S6. SLAN expression on monocytes from a XLA (BTK deficient) patient and a healthy control. Table SI. List of 92 inflammatory markers analyzed by NPX. Table SIV. Median percentage values (and range) for the different PBMC populations in the 7 patients. Data S1. Materials and methods. |
| bjh15516-sup-0002-TableS2.xlsxMS Excel, 15.9 KB | Table SII. RNAseq sample information. Sample donor (patient, PT), timepoint at which sample was taken (pre-treatment, pre; day 2/29, d2/29), compartment (lymph node, LN; peripheral blood, PB), gating used for FACs sorting (population), number of reads (total, uniquely mapped and % uniquely mapped) and final number of reads in the tag directories after all filtering (total Tags). |
| bjh15516-sup-0003-TableS3.xlsxMS Excel, 209.3 KB | Table SIII. Log10 quantile normalized read counts of differentially expressed genes shown on Fig 4A. Filled boxes indicate compartment and time-point of extraction for each sample. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
References
- Assarsson, E., Lundberg, M., Holmquist, G., Bjorkesten, J., Thorsen, S.B., Ekman, D., Eriksson, A., Rennel Dickens, E., Ohlsson, S., Edfeldt, G., Andersson, A.C., Lindstedt, P., Stenvang, J., Gullberg, M. & Fredriksson, S. (2014) Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS One, 9, e95192.
- Berglof, A., Turunen, J.J., Gissberg, O., Bestas, B., Blomberg, K.E. & Smith, C.I.E. (2013) Agammaglobulinemia: causative mutations and their implications for novel therapies. Expert Review of Clinical Immunology, 9, 1205–1221.
- Buchner, M., Baer, C., Prinz, G., Dierks, C., Burger, M., Zenz, T., Stilgenbauer, S., Jumaa, H., Veelken, H. & Zirlik, K. (2010) Spleen tyrosine kinase inhibition prevents chemokine- and integrin-mediated stromal protective effects in chronic lymphocytic leukemia. Blood, 115, 4497–4506.
- Burger, J.A., Quiroga, M.P., Hartmann, E., Burkle, A., Wierda, W.G., Keating, M.J. & Rosenwald, A. (2009) High-level expression of the T-cell chemokines CCL3 and CCL4 by chronic lymphocytic leukemia B cells in nurselike cell cocultures and after BCR stimulation. Blood, 113, 3050–3058.
- Byrd, J.C., Harrington, B., O'Brien, S., Jones, J.A., Schuh, A., Devereux, S., Chaves, J., Wierda, W.G., Awan, F.T., Brown, J.R., Hillmen, P., Stephens, D.M., Ghia, P., Barrientos, J.C., Pagel, J.M., Woyach, J., Johnson, D., Huang, J., Wang, X., Kaptein, A., Lannutti, B.J., Covey, T., Fardis, M., McGreivy, J., Hamdy, A., Rothbaum, W., Izumi, R., Diacovo, T.G., Johnson, A.J. & Furman, R.R. (2016) Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. New England Journal of Medicine, 374, 323–332.
- Calissano, C., Damle, R.N., Marsilio, S., Yan, X.J., Yancopoulos, S., Hayes, G., Emson, C., Murphy, E.J., Hellerstein, M.K., Sison, C., Kaufman, M.S., Kolitz, J.E., Allen, S.L., Rai, K.R., Ivanovic, I., Dozmorov, I.M., Roa, S., Scharff, M.D., Li, W. & Chiorazzi, N. (2011) Intraclonal complexity in chronic lymphocytic leukemia: fractions enriched in recently born/divided and older/quiescent cells. Molecular Medicine, 17, 1374–1382.
- Cheng, S., Ma, J., Guo, A., Lu, P., Leonard, J.P., Coleman, M., Liu, M., Buggy, J.J., Furman, R.R. & Wang, Y.L. (2014) BTK inhibition targets in vivo CLL proliferation through its effects on B-cell receptor signaling activity. Leukemia, 28, 649–657.
- Chung, J.B., Sater, R.A., Fields, M.L., Erikson, J. & Monroe, J.G. (2002) CD23 defines two distinct subsets of immature B cells which differ in their responses to T cell help signals. International Immunology, 14, 157–166.
- Da Roit, F., Engelberts, P.J., Taylor, R.P., Breij, E.C., Gritti, G., Rambaldi, A., Introna, M., Parren, P.W., Beurskens, F.J. & Golay, J. (2015) Ibrutinib interferes with the cell-mediated anti-tumor activities of therapeutic CD20 antibodies: implications for combination therapy. Haematologica, 100, 77–86.
- Davids, M.S. & Burger, J.A. (2012) Cell trafficking in chronic lymphocytic leukemia. Open Journal of Hematology, 3, (S1).
- Deshmane, S.L., Kremlev, S., Amini, S. & Sawaya, B.E. (2009) Monocyte chemoattractant protein-1 (MCP-1): an overview. Journal of Interferon & Cytokine Research, 29, 313–326.
- Drennan, S., D'Avola, A., Gao, Y., Weigel, C., Chrysostomou, E., Steele, A.J., Zenz, T., Plass, C., Johnson, P.W., Williams, A.P., Packham, G., Stevenson, F.K., Oakes, C.C. & Forconi, F. (2017) IL-10 production by CLL cells is enhanced in the anergic IGHV mutated subset and associates with reduced DNA methylation of the IL10 locus. Leukemia, 31, 1686–1694.
- Dubovsky, J.A., Beckwith, K.A., Natarajan, G., Woyach, J.A., Jaglowski, S., Zhong, Y., Hessler, J.D., Liu, T.M., Chang, B.Y., Larkin, K.M., Stefanovski, M.R., Chappell, D.L., Frissora, F.W., Smith, L.L., Smucker, K.A., Flynn, J.M., Jones, J.A., Andritsos, L.A., Maddocks, K., Lehman, A.M., Furman, R., Sharman, J., Mishra, A., Caligiuri, M.A., Satoskar, A.R., Buggy, J.J., Muthusamy, N., Johnson, A.J. & Byrd, J.C. (2013) Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood, 122, 2539–2549.
- Herishanu, Y., Perez-Galan, P., Liu, D., Biancotto, A., Pittaluga, S., Vire, B., Gibellini, F., Njuguna, N., Lee, E., Stennett, L., Raghavachari, N., Liu, P., McCoy, J.P., Raffeld, M., Stetler-Stevenson, M., Yuan, C., Sherry, R., Arthur, D.C., Maric, I., White, T., Marti, G.E., Munson, P., Wilson, W.H. & Wiestner, A. (2011) The lymph node microenvironment promotes B-cell receptor signaling, NF-kappaB activation, and tumor proliferation in chronic lymphocytic leukemia. Blood, 117, 563–574.
- Herman, S.E., Gordon, A.L., Hertlein, E., Ramanunni, A., Zhang, X., Jaglowski, S., Flynn, J., Jones, J., Blum, K.A., Buggy, J.J., Hamdy, A., Johnson, A.J. & Byrd, J.C. (2011) Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood, 117, 6287–6296.
- Herman, S.E., Mustafa, R.Z., Gyamfi, J.A., Pittaluga, S., Chang, S., Chang, B., Farooqui, M. & Wiestner, A. (2014a) Ibrutinib inhibits BCR and NF-kappaB signaling and reduces tumor proliferation in tissue-resident cells of patients with CLL. Blood, 123, 3286–3295.
- Herman, S.E., Niemann, C.U., Farooqui, M., Jones, J., Mustafa, R.Z., Lipsky, A., Saba, N., Martyr, S., Soto, S., Valdez, J., Gyamfi, J.A., Maric, I., Calvo, K.R., Pedersen, L.B., Geisler, C.H., Liu, D., Marti, G.E., Aue, G. & Wiestner, A. (2014b) Ibrutinib-induced lymphocytosis in patients with chronic lymphocytic leukemia: correlative analyses from a phase II study. Leukemia, 28, 2188–2196.
- Hewamana, S., Lin, T.T., Rowntree, C., Karunanithi, K., Pratt, G., Hills, R., Fegan, C., Brennan, P. & Pepper, C. (2009) Rel a is an independent biomarker of clinical outcome in chronic lymphocytic leukemia. Journal of Clinical Oncology, 27, 763–769.
- Kriston, C., Bodor, C., Szenthe, K., Banati, F., Bankuti, B., Csernus, B., Reiniger, L., Csomor, J., Matolcsy, A. & Barna, G. (2015) Low CD23 expression correlates with high CD38 expression and the presence of trisomy 12 in CLL. Hematological Oncology, 35, 58–63.
- Landau, D.A., Tausch, E., Taylor-Weiner, A.N., Stewart, C., Reiter, J.G., Bahlo, J., Kluth, S., Bozic, I., Lawrence, M., Bottcher, S., Carter, S.L., Cibulskis, K., Mertens, D., Sougnez, C.L., Rosenberg, M., Hess, J.M., Edelmann, J., Kless, S., Kneba, M., Ritgen, M., Fink, A., Fischer, K., Gabriel, S., Lander, E.S., Nowak, M.A., Dohner, H., Hallek, M., Neuberg, D., Getz, G., Stilgenbauer, S. & Wu, C.J. (2015) Mutations driving CLL and their evolution in progression and relapse. Nature, 526, 525–530.
- Maffei, R., Bulgarelli, J., Fiorcari, S., Bertoncelli, L., Martinelli, S., Guarnotta, C., Castelli, I., Deaglio, S., Debbia, G., De Biasi, S., Bonacorsi, G., Zucchini, P., Narni, F., Tripodo, C., Luppi, M., Cossarizza, A. & Marasca, R. (2013) The monocytic population in chronic lymphocytic leukemia shows altered composition and deregulation of genes involved in phagocytosis and inflammation. Haematologica, 98, 1115–1123.
- Mageed, R.A., Garaud, S., Taher, T.E., Parikh, K., Pers, J.O., Jamin, C., Renaudineau, Y. & Youinou, P. (2012) CD5 expression promotes multiple intracellular signaling pathways in B lymphocyte. Autoimmunity Reviews, 11, 795–798.
- Muggen, A.F., Singh, S.P., Hendriks, R.W. & Langerak, A.W. (2016) Targeting signaling pathways in chronic lymphocytic leukemia. Current Cancer Drug Targets, 16, 669–688.
- Niemann, C.U., Herman, S.E., Maric, I., Gomez-Rodriguez, J., Biancotto, A., Chang, B.Y., Martyr, S., Stetler-Stevenson, M., Yuan, C.M., Calvo, K.R., Braylan, R.C., Valdez, J., Lee, Y.S., Wong, D.H., Jones, J., Sun, C., Marti, G.E., Farooqui, M.Z. & Wiestner, A. (2016) Disruption of in vivo chronic lymphocytic leukemia tumor-microenvironment interactions by ibrutinib–findings from an investigator-initiated phase ii study. Clinical Cancer Research, 22, 1572–1582.
- Palma, M., Gentilcore, G., Heimersson, K., Mozaffari, F., Nasman-Glaser, B., Young, E., Rosenquist, R., Hansson, L., Osterborg, A. & Mellstedt, H. (2017) T cells in chronic lymphocytic leukemia display dysregulated expression of immune checkpoints and activation markers. Haematologica, 102, 562–572.
- Pavlasova, G., Borsky, M., Seda, V., Cerna, K., Osickova, J., Doubek, M., Mayer, J., Calogero, R., Trbusek, M., Pospisilova, S., Davids, M.S., Kipps, T.J., Brown, J.R. & Mraz, M. (2016) Ibrutinib inhibits CD20 upregulation on CLL B cells mediated by the CXCR4/SDF-1 axis. Blood, 128, 1609–1613.
- Pede, V., Rombout, A., Vermeire, J., Naessens, E., Mestdagh, P., Robberecht, N., Vanderstraeten, H., Van Roy, N., Vandesompele, J., Speleman, F., Philippe, J. & Verhasselt, B. (2013) CLL cells respond to B-Cell receptor stimulation with a microRNA/mRNA signature associated with MYC activation and cell cycle progression. PLoS One, 8, e60275.
- Pepper, C., Buggins, A.G., Jones, C.H., Walsby, E.J., Forconi, F., Pratt, G., Devereux, S., Stevenson, F.K. & Fegan, C. (2015) Phenotypic heterogeneity in IGHV-mutated CLL patients has prognostic impact and identifies a subset with increased sensitivity to BTK and PI3Kdelta inhibition. Leukemia, 29, 744–747.
- Perez-Andres, M., Paiva, B., Nieto, W.G., Caraux, A., Schmitz, A., Almeida, J., Vogt, R.F. Jr, Marti, G.E., Rawstron, A.C., Van Zelm, M.C., Van Dongen, J.J., Johnsen, H.E., Klein, B. & Orfao, A. (2010) Human peripheral blood B-cell compartments: a crossroad in B-cell traffic. Cytometry. Part B, Clinical Cytometry, 78 (Suppl 1), 47–60.
- Renaudineau, Y., Nedellec, S., Berthou, C., Lydyard, P.M., Youinou, P. & Pers, J.O. (2005) Role of B-cell antigen receptor-associated molecules and lipid rafts in CD5-induced apoptosis of B CLL cells. Leukemia, 19, 223–229.
- Saulep-Easton, D., Vincent, F.B., Le Page, M., Wei, A., Ting, S.B., Croce, C.M., Tam, C. & Mackay, F. (2014) Cytokine-driven loss of plasmacytoid dendritic cell function in chronic lymphocytic leukemia. Leukemia, 28, 2005–2015.
- Schulz, A., Toedt, G., Zenz, T., Stilgenbauer, S., Lichter, P. & Seiffert, M. (2011) Inflammatory cytokines and signaling pathways are associated with survival of primary chronic lymphocytic leukemia cells in vitro: a dominant role of CCL2. Haematologica, 96, 408–416.
- Sivina, M., Hartmann, E., Kipps, T.J., Rassenti, L., Krupnik, D., Lerner, S., LaPushin, R., Xiao, L., Huang, X., Werner, L., Neuberg, D., Kantarjian, H., O'Brien, S., Wierda, W.G., Keating, M.J., Rosenwald, A. & Burger, J.A. (2011) CCL3 (MIP-1alpha) plasma levels and the risk for disease progression in chronic lymphocytic leukemia. Blood, 117, 1662–1669.
- Skarzynski, M., Niemann, C.U., Lee, Y.S., Martyr, S., Maric, I., Salem, D., Stetler-Stevenson, M., Marti, G.E., Calvo, K.R., Yuan, C., Valdez, J., Soto, S., Farooqui, M.Z., Herman, S.E. & Wiestner, A. (2016) Interactions between ibrutinib and anti-CD20 antibodies: competing effects on the outcome of combination therapy. Clinical Cancer Research, 22, 86–95.
- Tai, Y.T., Chang, B.Y., Kong, S.Y., Fulciniti, M., Yang, G., Calle, Y., Hu, Y., Lin, J., Zhao, J.J., Cagnetta, A., Cea, M., Sellitto, M.A., Zhong, M.Y., Wang, Q., Acharya, C., Carrasco, D.R., Buggy, J.J., Elias, L., Treon, S.P., Matsui, W., Richardson, P., Munshi, N.C. & Anderson, K.C. (2012) Bruton tyrosine kinase inhibition is a novel therapeutic strategy targeting tumor in the bone marrow microenvironment in multiple myeloma. Blood, 120, 1877–1887.
- Vetrie, D., Vorechovsky, I., Sideras, P., Holland, J., Davies, A., Flinter, F., Hammarstrom, L., Kinnon, C., Levinsky, R., Bobrow, M., Smith, C.I.E. & Bentley, D.R. (1993) The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature, 361, 226–233.
- Wong, K.L., Yeap, W.H., Tai, J.J., Ong, S.M., Dang, T.M. & Wong, S.C. (2012) The three human monocyte subsets: implications for health and disease. Immunologic Research, 53, 41–57.
- Woyach, J.A., Smucker, K., Smith, L.L., Lozanski, A., Zhong, Y., Ruppert, A.S., Lucas, D., Williams, K., Zhao, W., Rassenti, L., Ghia, E., Kipps, T.J., Mantel, R., Jones, J., Flynn, J., Maddocks, K., O'Brien, S., Furman, R.R., James, D.F., Clow, F., Lozanski, G., Johnson, A.J. & Byrd, J.C. (2014) Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy. Blood, 123, 1810–1817.
- Yang, L., Zhao, T., Shi, X., Nakhaei, P., Wang, Y., Sun, Q., Hiscott, J. & Lin, R. (2009) Functional analysis of a dominant negative mutation of interferon regulatory factor 5. PLoS One, 4, e5500.
- Yeomans, A., Thirdborough, S.M., Valle-Argos, B., Linley, A., Krysov, S., Hidalgo, M.S., Leonard, E., Ishfaq, M., Wagner, S.D., Willis, A.E., Steele, A.J., Stevenson, F.K., Forconi, F., Coldwell, M.J. & Packham, G. (2016) Engagement of the B-cell receptor of chronic lymphocytic leukemia cells drives global and MYC-specific mRNA translation. Blood, 127, 449–457.
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