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These mice, designated iMyc<jats:sup>E\u03bc<\/jats:sup>, readily develop B-cell lymphoma. To study the mechanism of Myc-induced lymphoma, we analyzed signaling pathways in lymphoblastic B-cell lymphomas (LBLs) from iMyc<jats:sup>E\u03bc<\/jats:sup> mice, and an LBL-derived cell line, iMyc<jats:sup>E\u03bc<\/jats:sup>-1.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Nuclear factor-\u03baB (NF-\u03baB) and signal transducer and activator of transcription 3 (STAT3) were constitutively activated in iMyc<jats:sup>E\u03bc<\/jats:sup> mice, not only in LBLs but also in the splenic B-lymphocytes of young animals months before tumors developed. Moreover, inhibition of either transcription factor in iMyc<jats:sup>E\u03bc<\/jats:sup>-1 cells suppressed growth and caused apoptosis, and the abrogation of NF-\u03baB activity reduced DNA binding by both STAT3 and Myc, as well as Myc expression. Inhibition of STAT3 signaling eliminated the activity of both NF-\u03baB and Myc, and resulted in a corresponding decrease in the level of Myc. Thus, in iMyc<jats:sup>E\u03bc<\/jats:sup>-1 cells NF-\u03baB and STAT3 are co-dependent and can both regulate Myc. Consistent with this, NF-\u03baB and phosphorylated STAT3 were physically associated with one another. In addition, LBLs and iMyc<jats:sup>E\u03bc<\/jats:sup>-1 cells also showed constitutive AKT phosphorylation. Blocking AKT activation by inhibiting PI3K reduced iMyc<jats:sup>E\u03bc<\/jats:sup>-1 cell proliferation and caused apoptosis, via downregulation of NF-\u03baB and STAT3 activity and a reduction of Myc levels. Co-treatment with NF-\u03baB, STAT3 or\/and PI3K inhibitors led to additive inhibition of iMyc<jats:sup>E\u03bc<\/jats:sup>-1 cell proliferation, suggesting that these signaling pathways converge.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our findings support the notion that constitutive activation of NF-\u03baB and STAT3 depends on upstream signaling through PI3K, and that this activation is important for cell survival and proliferation, as well as for maintaining the level of Myc. Together, these data implicate crosstalk among NF-\u03baB, STAT3 and PI3K in the development of iMyc<jats:sup>E\u03bc<\/jats:sup> B-cell lymphomas.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1476-4598-9-97","type":"journal-article","created":{"date-parts":[[2010,4,30]],"date-time":"2010-04-30T18:16:10Z","timestamp":1272651370000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":103,"title":["NF-\u03baB\/STAT3\/PI3K signaling crosstalk in iMycE\u03bc B lymphoma"],"prefix":"10.1186","volume":"9","author":[{"given":"Seong-Su","family":"Han","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hwakyung","family":"Yun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong-Ju","family":"Son","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Van S.","family":"Tompkins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liangping","family":"Peng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seung-Tae","family":"Chung","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joong-Su","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eun-Sung","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siegfried","family":"Janz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2010,4,30]]},"reference":[{"key":"612_CR1","doi-asserted-by":"publisher","first-page":"2961","DOI":"10.1172\/JCI119849","volume":"100","author":"RC Bargou","year":"1997","unstructured":"Bargou RC, Emmerich F, Krappmann D, Bommert K, Mapara MY, Arnold W, Royer HD, Grinstein E, Greiner A, Scheidereit C, D\u00f6rken B: Constitutive nuclear factor-kappaB-RelA activation is required for proliferation and survival of Hodgkin's disease tumor cells. 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