{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T20:29:41Z","timestamp":1779136181681,"version":"3.51.4"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2019,10,1]],"date-time":"2019-10-01T00:00:00Z","timestamp":1569888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2019,10,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Despite the emergence of small molecule inhibitors, current treatment strategies for chronic lymphocytic leukemia (CLL) are not curative, and the search for new therapeutic modalities continues. Prosurvival signaling derived from the microenvironment is often mediated via JAK signaling. However, whether JAK inhibitors are useful in CLL therapy has not been studied extensively. JAK inhibitors are valuable therapeutic agents in myelofibrosis and show promising results in graft-versus-host-disease. However, JAK inhibition is associated with an increased infection risk, presumably because of the effect on other immune cells, a feature shared with other kinase inhibitors used for CLL treatment, such as the BTK inhibitor ibrutinib and the PI3K\u03b4 inhibitor idelalisib. We compared functional effects of the JAK1\/2 inhibitors momelotinib and ruxolitinib, the BTK inhibitors ibrutinib and tirabrutinib, and PI3K\u03b4 inhibitor idelalisib on malignant CLL cells but also on healthy human T, B, and NK lymphocytes. We found several interesting differences among the inhibitors, apart from expected and well-known effects. Momelotinib but not ruxolitinib blocked cytokine-induced proliferation of CLL cells. Momelotinib also reduced BCR signaling, in contrast to ruxolitinib, indicating that these JAK inhibitors in fact have a distinct target spectrum. In contrast to tirabrutinib, ibrutinib had inhibitory effects on T cell activation, probably because of ITK inhibition. Remarkably, both BTK inhibitors stimulated IFN-\u03b3 production in a mixed lymphocyte reaction. Collectively, our results demonstrate that kinase inhibitors directed at identical targets may have differential effects on lymphocyte function. Their unique profile could be strategically employed to balance desired versus unwanted lymphocyte inhibition.<\/jats:p>","DOI":"10.4049\/jimmunol.1900321","type":"journal-article","created":{"date-parts":[[2019,9,11]],"date-time":"2019-09-11T20:05:18Z","timestamp":1568232318000},"page":"2100-2109","source":"Crossref","is-referenced-by-count":18,"title":["Dissection of the Effects of JAK and BTK Inhibitors on the Functionality of Healthy and Malignant Lymphocytes"],"prefix":"10.1093","volume":"203","author":[{"given":"Tom","family":"Hofland","sequence":"first","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, University of Amsterdam , 1105 AZ Amsterdam ,","place":["the Netherlands"]},{"name":"Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam , 1105 AZ Amsterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Iris","family":"de Weerdt","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, University of Amsterdam , 1105 AZ Amsterdam ,","place":["the Netherlands"]},{"name":"Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam , 1105 AZ Amsterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hanneke","family":"ter Burg","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, University of Amsterdam , 1105 AZ Amsterdam ,","place":["the Netherlands"]},{"name":"Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam , 1105 AZ Amsterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renate","family":"de Boer","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, University of Amsterdam , 1105 AZ Amsterdam ,","place":["the Netherlands"]},{"name":"Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam , 1105 AZ Amsterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stacey","family":"Tannheimer","sequence":"additional","affiliation":[{"name":"Gilead Sciences , Foster City, CA 94404"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanne H","family":"Tonino","sequence":"additional","affiliation":[{"name":"Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam , 1105 AZ Amsterdam ,","place":["the Netherlands"]},{"name":"Lymphoma and Myeloma Center \u00a0 1105 AZ Amsterdam, Amsterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arnon P","family":"Kater","sequence":"additional","affiliation":[{"name":"Department of Hematology, Cancer Center Amsterdam, Amsterdam University Medical Centers, University of Amsterdam , 1105 AZ Amsterdam ,","place":["the Netherlands"]},{"name":"Lymphoma and Myeloma Center \u00a0 1105 AZ Amsterdam, Amsterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Eldering","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Centers, University of Amsterdam , 1105 AZ Amsterdam ,","place":["the Netherlands"]},{"name":"Lymphoma and Myeloma Center \u00a0 1105 AZ Amsterdam, Amsterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2019,10,15]]},"reference":[{"key":"2025030417543078200_r1","doi-asserted-by":"crossref","first-page":"16096","DOI":"10.1038\/nrdp.2016.96","article-title":"Chronic lymphocytic leukaemia","volume":"3","author":"Kipps","year":"2017","journal-title":"Nat. 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