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Non-Hodgkin Lymphoma
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
Ferrata Storti Foundation
Haematologica 2020 Volume 105(5):1361-1368
   Linfeng Chen,1,2 Jing Ouyang,1* Kirsty Wienand,1* Kamil Bojarczuk,1,3* Yansheng Hao,1,4 Bjoern Chapuy,1,5 Donna Neuberg,6 Przemyslaw Juszczynski,1,3 Lee N. Lawton,1 Scott J. Rodig,7 Stefano Monti8 and Margaret A. Shipp1
1Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; 2Current address: H3 Biomedicine, Cambridge, MA, USA; 3Current address: Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland; 4Current Address: Department of Pathology, Mount Sinai Hospital,
 New York, NY, USA; 5Current Address: Department of Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany; 6Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, USA; 7Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA and 8Section of Computational Biomedicine, Boston University School of Medicine, Boston, MA, USA
*JO, KW and KB contributed equally to this work.
 ABSTRACT
B-cell receptor (BCR) signaling pathway components represent promis- ing 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 prox- imal 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, molec- ular 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 migra- tion. Select PI3K isoform inhibitors also augmented SDF-1α induced chemotaxis. These data define CXCR4 upregulation as an indicator of sen- sitivity to BCR/PI3K blockade and identify CXCR4 signaling as a potential resistance mechanism in BCR-dependent DLBCLs.
Introduction
Diffuse large-B-cell lymphomas (DLBCLs) are clinically and genetically hetero- geneous diseases.1 Our previous studies demonstrated that a subset of DLBCLs rely upon B-cell receptor (BCR)-dependent survival signals.2,3 BCR signaling acti- vates proximal pathway components including the spleen tyrosine kinase (SYK) and downstream effectors such as phosphatidylinositol-3-kinase (PI3K)/AKT and the Bruton’s tyrosine kinase (BTK)/ nuclear factor-κB (NF-κB).3,4 In prior studies, we, and others, characterized distinct BCR/PI3K-dependent viability pathways in DLBCL cell lines and primary tumors with low- or high-baseline NF-κB activity
   Correspondence:
MARGARET A. SHIPP
margaret_shipp@dfci.harvard.edu
Received: January 7, 2019. Accepted: September 26, 2019. Pre-published: October 3, 2019.
doi:10.3324/haematol.2019.216218
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/1361
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