CCL3 and CCL4 are biomarkers for B cell receptor pathway activation and prognostic serum markers in diffuse large B cell lymphoma

Koichi Takahashi, Mariela Sivina, Julia Hoellenriegel, Yasuhiro Oki, Fredrick B. Hagemeister, Luis Fayad, Jorge E. Romaguera, Nathan Fowler, Michelle A. Fanale, Larry W. Kwak, Felipe Samaniego, Sattva Neelapu, Lianchun Xiao, Xuelin Huang, Hagop Kantarjian, Michael J. Keating, William Wierda, Kai Fu, Wing C. Chan, Julie Marie VoseSusan O'Brien, Richard E. Davis, Jan A. Burger

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

B cell receptor (BCR) signalling is an important pathway in diffuse large B cell lymphoma (DLBCL). In response to BCR triggering, normal and malignant B cells secrete the chemokines CCL3 and CCL4 to attract accessory cells to the tissue microenvironment. We measured CCL3 and CCL4 serum concentrations in 102 patients with newly diagnosed DLBCL by enzyme-linked immunosorbent assay, investigated their prognostic impact and validated our findings in an independent cohort of 51 patient samples. We also tested CCL3 and CCL4 secretion by DLBCL cells, and the influence of BTK inhibitors on the secretion of these chemokines. High CCL3 (≥40 pg/ml) serum concentrations correlated with higher international prognostic index, lactate dehydrogenase and β2 microglobulin, as did CCL4 (≥180 pg/ml) with advanced Ann Arbor stages. High CCL3 levels correlated with significantly shorter progression-free and overall survival. The in vitro studies demonstrated that activated B cell-like, but not germinal centre B cell-like DLBCL cells, secrete high levels of CCL3 and CCL4 after BCR triggering, which was exquisitely sensitive to BCR pathway inhibition. These findings support CCL3 and CCL4 protein concentrations as biomarkers for BCR pathway activation and prognosis in DLBCL.

Original languageEnglish (US)
Pages (from-to)726-735
Number of pages10
JournalBritish Journal of Haematology
Volume171
Issue number5
DOIs
StatePublished - Dec 1 2015

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Lymphoma, Large B-Cell, Diffuse
B-Lymphocytes
Biomarkers
Chemokine CCL4
Chemokine CCL3
Germinal Center
Serum
Chemokines
Disease-Free Survival
Enzyme-Linked Immunosorbent Assay

Keywords

  • Chemokines
  • Diffuse large B-cell lymphoma
  • Lymphoma

ASJC Scopus subject areas

  • Hematology

Cite this

Takahashi, K., Sivina, M., Hoellenriegel, J., Oki, Y., Hagemeister, F. B., Fayad, L., ... Burger, J. A. (2015). CCL3 and CCL4 are biomarkers for B cell receptor pathway activation and prognostic serum markers in diffuse large B cell lymphoma. British Journal of Haematology, 171(5), 726-735. https://doi.org/10.1111/bjh.13659

CCL3 and CCL4 are biomarkers for B cell receptor pathway activation and prognostic serum markers in diffuse large B cell lymphoma. / Takahashi, Koichi; Sivina, Mariela; Hoellenriegel, Julia; Oki, Yasuhiro; Hagemeister, Fredrick B.; Fayad, Luis; Romaguera, Jorge E.; Fowler, Nathan; Fanale, Michelle A.; Kwak, Larry W.; Samaniego, Felipe; Neelapu, Sattva; Xiao, Lianchun; Huang, Xuelin; Kantarjian, Hagop; Keating, Michael J.; Wierda, William; Fu, Kai; Chan, Wing C.; Vose, Julie Marie; O'Brien, Susan; Davis, Richard E.; Burger, Jan A.

In: British Journal of Haematology, Vol. 171, No. 5, 01.12.2015, p. 726-735.

Research output: Contribution to journalArticle

Takahashi, K, Sivina, M, Hoellenriegel, J, Oki, Y, Hagemeister, FB, Fayad, L, Romaguera, JE, Fowler, N, Fanale, MA, Kwak, LW, Samaniego, F, Neelapu, S, Xiao, L, Huang, X, Kantarjian, H, Keating, MJ, Wierda, W, Fu, K, Chan, WC, Vose, JM, O'Brien, S, Davis, RE & Burger, JA 2015, 'CCL3 and CCL4 are biomarkers for B cell receptor pathway activation and prognostic serum markers in diffuse large B cell lymphoma', British Journal of Haematology, vol. 171, no. 5, pp. 726-735. https://doi.org/10.1111/bjh.13659
Takahashi, Koichi ; Sivina, Mariela ; Hoellenriegel, Julia ; Oki, Yasuhiro ; Hagemeister, Fredrick B. ; Fayad, Luis ; Romaguera, Jorge E. ; Fowler, Nathan ; Fanale, Michelle A. ; Kwak, Larry W. ; Samaniego, Felipe ; Neelapu, Sattva ; Xiao, Lianchun ; Huang, Xuelin ; Kantarjian, Hagop ; Keating, Michael J. ; Wierda, William ; Fu, Kai ; Chan, Wing C. ; Vose, Julie Marie ; O'Brien, Susan ; Davis, Richard E. ; Burger, Jan A. / CCL3 and CCL4 are biomarkers for B cell receptor pathway activation and prognostic serum markers in diffuse large B cell lymphoma. In: British Journal of Haematology. 2015 ; Vol. 171, No. 5. pp. 726-735.
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T1 - CCL3 and CCL4 are biomarkers for B cell receptor pathway activation and prognostic serum markers in diffuse large B cell lymphoma

AU - Takahashi, Koichi

AU - Sivina, Mariela

AU - Hoellenriegel, Julia

AU - Oki, Yasuhiro

AU - Hagemeister, Fredrick B.

AU - Fayad, Luis

AU - Romaguera, Jorge E.

AU - Fowler, Nathan

AU - Fanale, Michelle A.

AU - Kwak, Larry W.

AU - Samaniego, Felipe

AU - Neelapu, Sattva

AU - Xiao, Lianchun

AU - Huang, Xuelin

AU - Kantarjian, Hagop

AU - Keating, Michael J.

AU - Wierda, William

AU - Fu, Kai

AU - Chan, Wing C.

AU - Vose, Julie Marie

AU - O'Brien, Susan

AU - Davis, Richard E.

AU - Burger, Jan A.

PY - 2015/12/1

Y1 - 2015/12/1

N2 - B cell receptor (BCR) signalling is an important pathway in diffuse large B cell lymphoma (DLBCL). In response to BCR triggering, normal and malignant B cells secrete the chemokines CCL3 and CCL4 to attract accessory cells to the tissue microenvironment. We measured CCL3 and CCL4 serum concentrations in 102 patients with newly diagnosed DLBCL by enzyme-linked immunosorbent assay, investigated their prognostic impact and validated our findings in an independent cohort of 51 patient samples. We also tested CCL3 and CCL4 secretion by DLBCL cells, and the influence of BTK inhibitors on the secretion of these chemokines. High CCL3 (≥40 pg/ml) serum concentrations correlated with higher international prognostic index, lactate dehydrogenase and β2 microglobulin, as did CCL4 (≥180 pg/ml) with advanced Ann Arbor stages. High CCL3 levels correlated with significantly shorter progression-free and overall survival. The in vitro studies demonstrated that activated B cell-like, but not germinal centre B cell-like DLBCL cells, secrete high levels of CCL3 and CCL4 after BCR triggering, which was exquisitely sensitive to BCR pathway inhibition. These findings support CCL3 and CCL4 protein concentrations as biomarkers for BCR pathway activation and prognosis in DLBCL.

AB - B cell receptor (BCR) signalling is an important pathway in diffuse large B cell lymphoma (DLBCL). In response to BCR triggering, normal and malignant B cells secrete the chemokines CCL3 and CCL4 to attract accessory cells to the tissue microenvironment. We measured CCL3 and CCL4 serum concentrations in 102 patients with newly diagnosed DLBCL by enzyme-linked immunosorbent assay, investigated their prognostic impact and validated our findings in an independent cohort of 51 patient samples. We also tested CCL3 and CCL4 secretion by DLBCL cells, and the influence of BTK inhibitors on the secretion of these chemokines. High CCL3 (≥40 pg/ml) serum concentrations correlated with higher international prognostic index, lactate dehydrogenase and β2 microglobulin, as did CCL4 (≥180 pg/ml) with advanced Ann Arbor stages. High CCL3 levels correlated with significantly shorter progression-free and overall survival. The in vitro studies demonstrated that activated B cell-like, but not germinal centre B cell-like DLBCL cells, secrete high levels of CCL3 and CCL4 after BCR triggering, which was exquisitely sensitive to BCR pathway inhibition. These findings support CCL3 and CCL4 protein concentrations as biomarkers for BCR pathway activation and prognosis in DLBCL.

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