{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,3,5]],"date-time":"2025-03-05T05:44:08Z","timestamp":1741153448608,"version":"3.38.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2020,1,1]],"date-time":"2020-01-01T00:00:00Z","timestamp":1577836800000},"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":[[2020,1,15]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Balanced activity of kinases and phosphatases downstream of the BCR is essential for B cell differentiation and function and is disturbed in chronic lymphocytic leukemia (CLL). In this study, we employed IgH.TE\u03bc mice, which spontaneously develop CLL, and stable EMC CLL cell lines derived from these mice to explore the role of phosphatases in CLL. Genome-wide expression profiling comparing IgH.TE\u03bc CLL cells with wild-type splenic B cells identified 96 differentially expressed phosphatase genes, including SH2-containing inositol phosphatase (Ship2). We found that B cell\u2013specific deletion of Ship2, but not of its close homolog Ship1, significantly reduced CLL formation in IgH.TE\u03bc mice. Treatment of EMC cell lines with Ship1\/2 small molecule inhibitors resulted in the induction of caspase-dependent apoptosis. Using flow cytometry and Western blot analysis, we observed that blocking Ship1\/2 abrogated EMC cell survival by exerting dual effects on the BCR signaling cascade. On one hand, specific Ship1 inhibition enhanced calcium signaling and thereby abrogated an anergic response to BCR stimulation in CLL cells. On the other hand, concomitant Ship1\/Ship2 inhibition or specific Ship2 inhibition reduced constitutive activation of the mTORC1\/ribosomal protein S6 pathway and downregulated constitutive expression of the antiapoptotic protein Mcl-1, in both EMC cell lines and primary IgH.TE\u03bc CLL cells. Importantly, also in human CLL, we found overexpression of many phosphatases including SHIP2. Inhibition of SHIP1\/SHIP2 reduced cellular survival and S6 phosphorylation and enhanced basal calcium levels in human CLL cells. Taken together, we provide evidence that SHIP2 contributes to CLL pathogenesis in mouse and human CLL.<\/jats:p>","DOI":"10.4049\/jimmunol.1900153","type":"journal-article","created":{"date-parts":[[2019,12,13]],"date-time":"2019-12-13T20:14:18Z","timestamp":1576268058000},"page":"360-374","source":"Crossref","is-referenced-by-count":6,"title":["Overexpression of SH2-Containing Inositol Phosphatase Contributes to Chronic Lymphocytic Leukemia Survival"],"prefix":"10.1093","volume":"204","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2902-5899","authenticated-orcid":false,"given":"Simar","family":"Pal Singh","sequence":"first","affiliation":[{"name":"Department of Pulmonary Medicine , Erasmus MC, NL 3000 CA Rotterdam ,","place":["the Netherlands"]},{"name":"Department of Immunology, Erasmus MC , NL 3000 CA Rotterdam ,","place":["the Netherlands"]},{"name":"Postgraduate School Molecular Medicine, Erasmus MC , NL 3000 CA Rotterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marjolein J W","family":"de Bruijn","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine , Erasmus MC, NL 3000 CA Rotterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Catarina","family":"Velaso Gago da Gra\u00e7a","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine , Erasmus MC, NL 3000 CA Rotterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Odilia B J","family":"Corneth","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine , Erasmus MC, NL 3000 CA Rotterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasper","family":"Rip","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine , Erasmus MC, NL 3000 CA Rotterdam ,","place":["the 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G\u00e9n\u00e9tique Fonctionnelle, GIGA-Research Centre, Universit\u00e9 de Li\u00e8ge , 4000 Li\u00e8ge ,","place":["Belgium"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4720-7135","authenticated-orcid":false,"given":"William G","family":"Kerr","sequence":"additional","affiliation":[{"name":"Department of Microbiology and Immunology, SUNY Upstate Medical University , Syracuse, NY 13210"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Johanna","family":"ter Burg","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Academic Medical Center, University of Amsterdam , 1105 AZ Amsterdam ,","place":["the Netherlands"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric","family":"Eldering","sequence":"additional","affiliation":[{"name":"Department of Experimental Immunology, Academic Medical Center, University of Amsterdam , 1105 AZ Amsterdam ,","place":["the 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