Lymphoma cell survival and progression are putatively dependent on a specific microanatomic localization within secondary lymphoid organs. Despite compelling data correlating homeostatic chemokine receptor expression and human lymphoma pathogenesis, genetic models that either mimic lymphoma dissemination or dissect a crosstalk of lymphoma and stromal cells are missing. Applying the genetically tractable EMyc transgenic mouse model, we show that the chemokine receptor CCR7 regulates EMyc lymphoma homing to lymph nodes and distinctive microanatomic sites of the spleen. CCR7-controlled access of lymphoma cells to the splenic T-cell zone led to a significant survival advantage compared with CCR7-deficient lymphoma cells, which were excluded from this zone. Within the niche, lymphoma cells stimulated a reciprocal cross-talk with gp38 ؉ fibroblastic reticular cells. This reciprocal cooperation program was mediated by lymphoma B cellpresented lymphotoxin, which acted on lymphotoxin-␤-receptor-bearing stromal cells followed by alteration of stromal cellular composition. Cross-talk inhibition by lymphotoxin-␣ deletion and using a lymphotoxin-␤ receptor-immunoglobulin fusion protein impaired lymphoma growth. Thus, abrogation of CCR7-governed migration and of sustained lymphotoxin signaling could provide new targets in lymphoma therapy. (Blood. 2011;118(4):1020-1033) IntroductionThe crosstalk between lymphoid tumor cells and their microenvironment provides pivotal signals for the localization and progression of lymphoid malignancies. Thus, it has become increasingly important to define which molecular mechanisms allow the interactions between accessory cells and malignant B-cells and to identify the stromal cells that mediate such signals. 1,2 In E-Myc transgenic mice, a mouse model of Myc-driven aggressive human B-cell lymphoma, the precancerous state is characterized by excessive proliferation in conjunction with the onset of an apoptotic program within the bone marrow precursor and immature B-cell compartment. 3,4 Although the role of genetic lesions as steps toward cell autonomy and tumor growth has been appreciated, 5,6 in vivo the conditions for lymphoma cell lodging within secondary lymphoid organs (SLOs) remain to be addressed. Several in vitro studies or transfer models of human lymphoma cell lines into immunodeficient mice could demonstrate that a variety of cytokines, adhesion molecules, and growth factors were involved in the cross-talk at the stroma-lymphoma cell interface. 7,8 Clinical studies have correlated the involvement of chemokine receptors with nodal homing of B-cell non-Hodgkin (NHL) and Hodgkin lymphoma. 9,10 Conversely, lack of the major lymph node (LN) addressins, foremost the homeostatic chemokine receptors CXCR5 and CCR7, may predispose those tumor cells for extranodal dissemination instead. 11 In vivo, the dissemination of primary central nervous system lymphoma toward brain-expressed chemokine ligand CCL21 has been shown to be controlled by CCR7 expression. 12 Although this investigation consi...

† These authors contributed equally to this work.The small GTPase Rac1 is involved in multiple cytosolic functions but recent data point out that Rac1 also translocates to the nucleus to regulate signalling pathways that control gene expression and progression through the cell cycle. Here, we identify the nuclear import receptor karyopherin α2 (KPNA2) as a direct interaction partner of Rac1. The C-terminal polybasic region of Rac1 contains a nuclear localization signal (NLS), whereas Rac2 and Rac3 lack a functional NLS and do not bind to KPNA2. The presence of the NLS in Rac1 determines the specificity of the interaction and is a prerequisite for the nuclear import. Although this interaction is independent of the Rac1 GDP/GTP loading, the induction of the translocation requires Rac1 activation. The activation of Rac1 via the cytotoxic necrotizing factor 1 and the concurrent inhibition of its proteasomal degradation are crucial for the nuclear accumulation of Rac1. Conversely, the reduction of KPNA2 expression inhibits the nuclear import of Rac1. For the first time, our results show a direct interaction between Rac1 and KPNA2 and argue for a KPNA2-dependent nuclear import of Rac1. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis revealed that nuclear Rac1 coimmunoprecipitates with numerous proteins. In the nucleus, Rac1 may participate in a variety of so far uncharacterized processes.