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
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
Affiliations
Linfeng Chen
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Current address: H3 Biomedicine, Cambridge, MA, USA
Jing Ouyang
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Kirsty Wienand
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Kamil Bojarczuk
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Current address: Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
Yansheng Hao
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Current Address: Department of Pathology, Mount Sinai Hospital, New York, NY, USA
Bjoern Chapuy
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Current Address: Department of Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany
Donna Neuberg
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, USA
Przemyslaw Juszczynski
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA;Current address: Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland
Lee N. Lawton
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
Scott J. Rodig
Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA
Stefano Monti
Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA
Margaret A. Shipp
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
B-cell receptor (BCR) signaling pathway components represent promising treatment targets in multiple B-cell malignancies including diffuse large B-cell lymphoma (DLBCL). In in vitro and in vivo 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.
