The CXCR4-CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro

Katrin Pansy, Julia Feichtinger, Barbara Ehall, Barbara Uhl, Miriam Sedej, David Roula, Beata Pursche, Axel Wolf, Manuel Zoidl, Elisabeth Steinbauer, Verena Gruber, Hildegard T Greinix, Katharina T Prochazka, Gerhard G Thallinger, Akos Heinemann, Christine Beham-Schmid, Peter Neumeister, Tanja M Wrodnigg, Karoline Fechter, Alexander Ja Deutsch

Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

Abstract

In tumor cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.

Originalspracheenglisch
Aufsatznummer4740
FachzeitschriftInternational Journal of Molecular Sciences
Jahrgang20
Ausgabenummer19
DOIs
PublikationsstatusVeröffentlicht - 24 Sep 2019

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Lymphoma, Large B-Cell, Diffuse
Lymphoma
Cells
bone marrow
Bone
cultured cells
Genes
genes
Bone Marrow
Cell Line
Biopsy
Niacin
pathogenesis
Infiltration
Tumors
metastasis
infiltration
Neoplasms
Neoplasm Metastasis
Derivatives

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The CXCR4-CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro. / Pansy, Katrin; Feichtinger, Julia; Ehall, Barbara; Uhl, Barbara; Sedej, Miriam; Roula, David; Pursche, Beata; Wolf, Axel; Zoidl, Manuel; Steinbauer, Elisabeth; Gruber, Verena; Greinix, Hildegard T; Prochazka, Katharina T; Thallinger, Gerhard G; Heinemann, Akos; Beham-Schmid, Christine; Neumeister, Peter; Wrodnigg, Tanja M; Fechter, Karoline; Deutsch, Alexander Ja.

in: International Journal of Molecular Sciences , Jahrgang 20, Nr. 19, 4740, 24.09.2019.

Publikation: Beitrag in einer FachzeitschriftArtikelForschungBegutachtung

Pansy, K, Feichtinger, J, Ehall, B, Uhl, B, Sedej, M, Roula, D, Pursche, B, Wolf, A, Zoidl, M, Steinbauer, E, Gruber, V, Greinix, HT, Prochazka, KT, Thallinger, GG, Heinemann, A, Beham-Schmid, C, Neumeister, P, Wrodnigg, TM, Fechter, K & Deutsch, AJ 2019, 'The CXCR4-CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro' International Journal of Molecular Sciences , Jg. 20, Nr. 19, 4740. https://doi.org/10.3390/ijms20194740
Pansy, Katrin ; Feichtinger, Julia ; Ehall, Barbara ; Uhl, Barbara ; Sedej, Miriam ; Roula, David ; Pursche, Beata ; Wolf, Axel ; Zoidl, Manuel ; Steinbauer, Elisabeth ; Gruber, Verena ; Greinix, Hildegard T ; Prochazka, Katharina T ; Thallinger, Gerhard G ; Heinemann, Akos ; Beham-Schmid, Christine ; Neumeister, Peter ; Wrodnigg, Tanja M ; Fechter, Karoline ; Deutsch, Alexander Ja. / The CXCR4-CXCL12-Axis Is of Prognostic Relevance in DLBCL and Its Antagonists Exert Pro-Apoptotic Effects In Vitro. in: International Journal of Molecular Sciences . 2019 ; Jahrgang 20, Nr. 19.
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abstract = "In tumor cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.",
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AU - Pansy, Katrin

AU - Feichtinger, Julia

AU - Ehall, Barbara

AU - Uhl, Barbara

AU - Sedej, Miriam

AU - Roula, David

AU - Pursche, Beata

AU - Wolf, Axel

AU - Zoidl, Manuel

AU - Steinbauer, Elisabeth

AU - Gruber, Verena

AU - Greinix, Hildegard T

AU - Prochazka, Katharina T

AU - Thallinger, Gerhard G

AU - Heinemann, Akos

AU - Beham-Schmid, Christine

AU - Neumeister, Peter

AU - Wrodnigg, Tanja M

AU - Fechter, Karoline

AU - Deutsch, Alexander Ja

PY - 2019/9/24

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N2 - In tumor cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.

AB - In tumor cells of more than 20 different cancer types, the CXCR4-CXCL12-axis is involved in multiple key processes including proliferation, survival, migration, invasion, and metastasis. Since data on this axis in diffuse large B cell lymphoma (DLBCL) are inconsistent and limited, we comprehensively studied the CXCR4-CXCL12-axis in our DLBCL cohort as well as the effects of CXCR4 antagonists on lymphoma cell lines in vitro. In DLBCL, we observed a 140-fold higher CXCR4 expression compared to non-neoplastic controls, which was associated with poor clinical outcome. In corresponding bone marrow biopsies, we observed a correlation of CXCL12 expression and lymphoma infiltration rate as well as a reduction of CXCR4 expression in remission of bone marrow involvement after treatment. Additionally, we investigated the effects of three CXCR4 antagonists in vitro. Therefore, we used AMD3100 (Plerixafor), AMD070 (Mavorixafor), and WKI, the niacin derivative of AMD070, which we synthesized. WK1 demonstrated stronger pro-apoptotic effects than AMD070 in vitro and induced expression of pro-apoptotic genes of the BCL2-family in CXCR4-positive lymphoma cell lines. Finally, WK1 treatment resulted in the reduced expression of JNK-, ERK1/2- and NF-κB/BCR-target genes. These data indicate that the CXCR4-CXCL12-axis impacts the pathogenesis of DLBCL and represents a potential therapeutic target in aggressive lymphomas.

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