title: CCL3 and CCL4 are biomarkers for B cell receptor pathway activation and prognostic serum markers in diffuse large B cell lymphoma.
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.
authors.affiliation: Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.|Department of Haematology and Oncology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Mariela
authors.initials: M
authors.lastname: Sivina
authors.affiliation: Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Hoellenriegel
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Oki
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Fredrick B
authors.initials: FB
authors.lastname: Hagemeister
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Luis
authors.initials: L
authors.lastname: Fayad
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Romaguera
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Nathan
authors.initials: N
authors.lastname: Fowler
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Fanale
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Larry W
authors.initials: LW
authors.lastname: Kwak
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Felipe
authors.initials: F
authors.lastname: Samaniego
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sattva
authors.initials: S
authors.lastname: Neelapu
authors.affiliation: Department of Biostatistics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Lianchun
authors.initials: L
authors.lastname: Xiao
authors.affiliation: Department of Biostatistics, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Xuelin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.affiliation: Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: William
authors.initials: W
authors.lastname: Wierda
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Fu
authors.affiliation: Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
authors.forename: Wing C
authors.initials: WC
authors.lastname: Chan
authors.affiliation: Division of Oncology and Hematology, University of NebraskaMedical Center, Omaha, NE, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Vose
authors.affiliation: Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: O'Brien
authors.affiliation: Department of Lymphoma and Myeloma, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Davis
authors.affiliation: Department of Leukemia, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jan A
authors.initials: JA
authors.lastname: Burger
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000970:Antineoplastic Agents / Q000627:therapeutic use; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D054405:Chemokine CCL3 / Q000378:metabolism*; D054407:Chemokine CCL4 / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D004812:Epidemiologic Methods; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse / Q000175:diagnosis* / Q000188:drug therapy; D010880:Piperidines; D011379:Prognosis; D011720:Pyrazoles / Q000627:therapeutic use; D011743:Pyrimidines / Q000627:therapeutic use; D015398:Signal Transduction / Q000502:physiology
chemical_list: D000970:Antineoplastic Agents; D053265:B-Cell Activation Factor Receptor; D014408:Biomarkers, Tumor; C515429:CCL3 protein, human; C066507:CCL4 protein, human; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; C551803:ibrutinib; D000225:Adenine
keywords: chemokines; diffuse large B-cell lymphoma; lymphoma