Format

Send to

Choose Destination
Haematologica. 2019 Aug 30. pii: haematol.2019.216218. doi: 10.3324/haematol.2019.216218. [Epub ahead of print]

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.

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA.
2
Dana-Farber Cancer Institute and Institute of Hematology & Transfusion Medicine, Warsaw.
3
Dana-Farber Cancer Institute, Boston and Mount Sinai Hospital, New York.
4
Dana-Farber Cancer Institute, Boston and University Medical Center Göttingen.
5
Dept. of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, USA.
6
Dana-Farber Cancer Institute Boston and Institute of Hematology and Transfusion Medicine, Warsaw.
7
Department of Pathology, Brigham and Womens Hospital, Boston, USA.
8
Section of Computational Biomedicine, Boston University School of Medicine, Boston, USA.
9
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; margaret_shipp@dfci.harvard.edu.

Abstract

B-cell receptor signaling pathway components represent promising treatment targets in multiple B-cell malignancies including diffuse large B-cell lymphoma. In in vitro and in vivo model systems, a subset of diffuse large B-cell lymphomas depend upon B-cell receptor survival signals and respond to proximal B-cell receptor/phosphoinositide 3 kinase blockade. However, single-agent B-cell receptor pathway inhibitors have had more limited activity in patients with diffuse large B-cell lymphoma, underscoring the need for indicators of sensitivity to B-cell receptor blockade and insights into potential resistance mechanisms. Here, we report highly significant transcriptional upregulation of C-X-C chemokine receptor 4 in B-cell receptor-dependent diffuse large B-cell lymphoma cell lines and primary tumors following chemical spleen tyrosine kinase inhibition, molecular spleen tyrosine kinase depletion or chemical phosphoinositide 3 kinase blockade. Spleen tyrosine kinase or phosphoinositide 3 kinase inhibition also selectively upregulated cell surface C-X-C chemokine receptor 4 protein expression in B-cell receptor-dependent diffuse large B-cell lymphomas. C-X-C chemokine receptor 4 expression was directly modulated by forkhead box O1 via the phosphoinositide 3 kinase/protein kinase B/forkhead box O1 signaling axis. Following chemical spleen tyrosine kinase inhibition, all B-cell receptor-dependent diffuse large B-cell lymphomas exhibited significantly increased stromal cell-derived factor alpha induced chemotaxis, consistent with the role of C-X-C chemokine receptor 4 signaling in B-cell migration. Select phosphoinositide 3 kinase isoform inhibitors also augmented stromal cell-derived factor alpha induced chemotaxis. These data define C-X-C chemokine receptor 4 upregulation as an indicator of sensitivity to B-cell receptor/phosphoinositide 3 kinase blockade and identify C-X-C chemokine receptor 4 signaling as a potential resistance mechanism in B-cell receptor-dependent diffuse large B-cell lymphomas.

KEYWORDS:

Aggressive Non-Hodgkin's Lymphoma; Cytogenetics and Molecular Genetics; Lymphocytes

PMID:
31471373
DOI:
10.3324/haematol.2019.216218
Free full text

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center