@article{Linfeng Chen_Jing Ouyang_Kirsty Wienand_Kamil Bojarczuk_Yansheng Hao_Bjoern Chapuy_Donna Neuberg_Przemyslaw Juszczynski_Lee N. Lawton_Scott J. Rodig_Stefano Monti_Margaret A. Shipp_2020, place={Pavia, Italy}, title={CXCR4 upregulation is an indicator of sensitivity to B-cell receptor/PI3K blockade and a potential resistance mechanism in B-cell receptor-dependent diffuse large B-cell lymphomas}, volume={105}, url={https://haematologica.org/article/view/9391}, DOI={10.3324/haematol.2019.216218}, abstractNote={B-cell receptor (BCR) signaling pathway components represent promising treatment targets in multiple B-cell malignancies including diffuse large B-cell lymphoma (DLBCL). In <em>in vitro</em> and <em>in vivo</em&gt; model systems, a subset of DLBCLs depend upon BCR survival signals and respond to proximal BCR/phosphoinositide 3 kinase (PI3K) blockade. However, single-agent BCR pathway inhibitors have had more limited activity in patients with DLBCL, underscoring the need for indicators of sensitivity to BCR blockade and insights into potential resistance mechanisms. Here, we report highly significant transcriptional upregulation of C-X-C chemokine receptor 4 (CXCR4) in BCR-dependent DLBCL cell lines and primary tumors following chemical spleen tyrosine kinase (SYK) inhibition, molecular SYK depletion or chemical PI3K blockade. SYK or PI3K inhibition also selectively upregulated cell surface CXCR4 protein expression in BCR-dependent DLBCLs. CXCR4 expression was directly modulated by fork-head box O1 via the PI3K/protein kinase B/forkhead box O1 signaling axis. Following chemical SYK inhibition, all BCR-dependent DLBCLs exhibited significantly increased stromal cell-derived factor-1α (SDF-1α) induced chemotaxis, consistent with the role of CXCR4 signaling in B-cell migration. Select PI3K isoform inhibitors also augmented SDF-1α induced chemotaxis. These data define CXCR4 upregulation as an indicator of sensitivity to BCR/PI3K blockade and identify CXCR4 signaling as a potential resistance mechanism in BCR-dependent DLBCLs.}, number={5}, journal={Haematologica}, author={Linfeng Chen and Jing Ouyang and Kirsty Wienand and Kamil Bojarczuk and Yansheng Hao and Bjoern Chapuy and Donna Neuberg and Przemyslaw Juszczynski and Lee N. Lawton and Scott J. Rodig and Stefano Monti and Margaret A. Shipp}, year={2020}, month={May}, pages={1361-1368} }