{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:05:28Z","timestamp":1791309928986,"version":"4.3.1"},"reference-count":20,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2014,11,5]],"date-time":"2014-11-05T00:00:00Z","timestamp":1415145600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100005189","name":"Leukemia and Lymphoma Society","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100005189","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Br J Haematol"],"published-print":{"date-parts":[[2015,3]]},"abstract":"Summary<\/jats:title>CXCR<\/jats:styled-content>4<\/jats:italic>WHIM<\/jats:sup><\/jats:styled-content> frameshift and nonsense mutations follow MYD<\/jats:styled-content>88<\/jats:italic>L265P<\/jats:sup> as the most common somatic variants in W<\/jats:styled-content>aldenstr\u00f6m M<\/jats:styled-content>acroglobulinaemia (WM<\/jats:styled-content>), and impact clinical presentation and ibrutinib response. While the nonsense (CXCR<\/jats:styled-content>4<\/jats:italic>S338X<\/jats:sup>) mutation has been investigated, little is known about CXCR<\/jats:styled-content>4 frameshift (CXCR<\/jats:styled-content>4<\/jats:italic>FS<\/jats:sup>) mutations. We engineered WM<\/jats:styled-content> cells to express CXCR<\/jats:styled-content>4<\/jats:italic>FS<\/jats:sup> mutations present in patients, and compared their CXCL<\/jats:styled-content>12 (SDF<\/jats:styled-content>\u20101a) induced signalling and ibrutinib sensitivity to CXCR<\/jats:styled-content>4<\/jats:italic>wild\u2010type (WT)<\/jats:sup> and CXCR<\/jats:styled-content>4<\/jats:italic>S338X<\/jats:sup> cells. Following CXCL<\/jats:styled-content>12 stimulation, CXCR<\/jats:styled-content>4<\/jats:italic>FS<\/jats:sup> and CXCR<\/jats:styled-content>4<\/jats:italic>S338X<\/jats:sup> WM<\/jats:styled-content> cells showed impaired CXCR<\/jats:styled-content>4 receptor internalization, and enhanced AKT<\/jats:styled-content>1 (also termed AKT<\/jats:styled-content>) and MAPK<\/jats:styled-content>1 (also termed ERK<\/jats:styled-content>) activation versus CXCR<\/jats:styled-content><\/jats:italic>WT<\/jats:sup> cells (P<\/jats:italic>\u00a0<\u00a00\u00b705), though MAPK<\/jats:styled-content>1 activation was more prolonged in CXCR<\/jats:styled-content>4<\/jats:italic>S338X<\/jats:sup> cells (P<\/jats:italic>\u00a0<\u00a00\u00b705). CXCR<\/jats:styled-content>4<\/jats:italic>FS<\/jats:sup> and CXCR<\/jats:styled-content>4<\/jats:italic>S338X<\/jats:sup> cells, but not CXCR<\/jats:styled-content>4<\/jats:italic>WT<\/jats:sup> cells, were rescued from ibrutinib\u2010triggered apoptosis by CXCL<\/jats:styled-content>12 that was reversed by AKT<\/jats:styled-content>1, MAPK<\/jats:styled-content>1 or CXCR<\/jats:styled-content>4 antagonists. Treatment with an inhibitor that blocks MYD<\/jats:styled-content>88L265P<\/jats:sup> signalling triggered similar levels of apoptosis that was not abrogated by CXCL<\/jats:styled-content>12 treatment in CXCR<\/jats:styled-content>4<\/jats:italic>WT<\/jats:sup> and CXCR<\/jats:styled-content>4<\/jats:italic>WHIM<\/jats:sup> cells. These studies show a functional role for CXCR<\/jats:styled-content>4<\/jats:italic>FS<\/jats:sup> mutations in WM<\/jats:styled-content>, and provide a framework for the investigation of CXCR<\/jats:styled-content>4 antagonists with ibrutinib in CXCR<\/jats:styled-content>4<\/jats:italic>WHIM<\/jats:sup>\u2010mutated WM<\/jats:styled-content> patients. Direct inhibition of MYD<\/jats:styled-content>88L265P<\/jats:sup> signalling overcomes CXCL<\/jats:styled-content>12 triggered survival effects in CXCR<\/jats:styled-content>4<\/jats:italic>WHIM<\/jats:sup>\u2010mutated cells supporting a primary role for this survival pathway in WM<\/jats:styled-content>.<\/jats:p>","DOI":"10.1111\/bjh.13200","type":"journal-article","created":{"date-parts":[[2014,11,5]],"date-time":"2014-11-05T09:16:15Z","timestamp":1415178975000},"page":"701-707","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":105,"title":["CXCR<\/scp>4 <\/i>WHIM<\/scp>\u2010like frameshift and nonsense mutations promote ibrutinib resistance but do not supplant MYD<\/scp>88<\/i>L265P<\/sup>\u2010directed survival signalling in W<\/scp>aldenstr\u00f6m macroglobulinaemia cells"],"prefix":"10.1111","volume":"168","author":[{"given":"Yang","family":"Cao","sequence":"first","affiliation":[{"name":"Bing Center for Waldenstrom's Macroglobulinemia Dana Farber Cancer Institute Boston MA USA"},{"name":"Department of Medicine Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zachary R.","family":"Hunter","sequence":"additional","affiliation":[{"name":"Bing Center for Waldenstrom's Macroglobulinemia Dana Farber Cancer Institute Boston MA USA"},{"name":"Department of Pathology Boston University Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xia","family":"Liu","sequence":"additional","affiliation":[{"name":"Bing Center for Waldenstrom's Macroglobulinemia Dana Farber Cancer Institute Boston MA USA"},{"name":"Department of Medicine Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lian","family":"Xu","sequence":"additional","affiliation":[{"name":"Bing Center for Waldenstrom's Macroglobulinemia Dana Farber Cancer Institute Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guang","family":"Yang","sequence":"additional","affiliation":[{"name":"Bing Center for Waldenstrom's Macroglobulinemia Dana Farber Cancer Institute Boston MA USA"},{"name":"Department of Medicine Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Chen","sequence":"additional","affiliation":[{"name":"Bing Center for Waldenstrom's Macroglobulinemia Dana Farber Cancer Institute Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nickolas","family":"Tsakmaklis","sequence":"additional","affiliation":[{"name":"Bing Center for Waldenstrom's Macroglobulinemia Dana Farber Cancer Institute Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Kanan","sequence":"additional","affiliation":[{"name":"Bing Center for Waldenstrom's Macroglobulinemia Dana Farber Cancer Institute Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9490-7532","authenticated-orcid":false,"given":"Jorge J.","family":"Castillo","sequence":"additional","affiliation":[{"name":"Bing Center for Waldenstrom's Macroglobulinemia Dana Farber Cancer Institute Boston MA USA"},{"name":"Department of Medicine Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven P.","family":"Treon","sequence":"additional","affiliation":[{"name":"Bing Center for Waldenstrom's Macroglobulinemia Dana Farber Cancer Institute Boston MA USA"},{"name":"Department of Medicine Harvard Medical School Boston MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2014,11,5]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/bcj.2014.4"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2006.11.002"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M109.091173"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2014.187"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.2174\/156652411795677963"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1349-7006.2007.00388.x"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-09-525808"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/leu.2013.62"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-07-102103"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-05-092098"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2007-09-115170"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-09-527226"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0064975"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2012-06-436329"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-03-564583"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1200710"},{"key":"e_1_2_8_18_1","doi-asserted-by":"crossref","first-page":"Abstract 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