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Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor
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| Veröffentlicht in: | Blood 130(2017), 5, Seite 643-654 |
|---|---|
| Personen und Körperschaften: | , , , |
| Titel: | Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor/ Vera Münch, Luca Trentin, Julia Herzig, Salih Demir, Felix Seyfried, Johann M. Kraus, Hans A. Kestler, Rolf Köhler, Thomas F. E. Barth, Geertruy te Kronnie, Klaus-Michael Debatin, and Lüder H. Meyer |
| Format: | E-Book-Kapitel |
| Sprache: | Englisch |
| veröffentlicht: |
26 May 2017
|
| Gesamtaufnahme: |
: Blood, 130(2017), 5, Seite 643-654
, volume:130 |
| Quelle: | Verbunddaten SWB Lizenzfreie Online-Ressourcen |
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| 245 | 1 | 0 | |a Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor |c Vera Münch, Luca Trentin, Julia Herzig, Salih Demir, Felix Seyfried, Johann M. Kraus, Hans A. Kestler, Rolf Köhler, Thomas F. E. Barth, Geertruy te Kronnie, Klaus-Michael Debatin, and Lüder H. Meyer |
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| 520 | |a In acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is a major clinical concern. Despite nondetectable CNS leukemia in many cases, prophylactic CNS-directed conventional intrathecal chemotherapy is required for relapse-free survival, indicating subclinical CNS manifestation in most patients. However, CNS-directed therapy is associated with long-term sequelae, including neurocognitive deficits and secondary neoplasms. Therefore, molecular mechanisms and pathways mediating leukemia-cell entry into the CNS need to be understood to identify targets for prophylactic and therapeutic interventions and develop alternative CNS-directed treatment strategies. In this study, we analyzed leukemia-cell entry into the CNS using a primograft ALL mouse model. We found that primary ALL cells transplanted onto nonobese diabetic/severe combined immunodeficiency mice faithfully recapitulated clinical and pathological features of meningeal infiltration seen in patients with ALL. ALL cells that had entered the CNS and were infiltrating the meninges were characterized by high expression of vascular endothelial growth factor A (VEGF). Although cellular viability, growth, proliferation, and survival of ALL cells were found to be independent of VEGF, transendothelial migration through CNS microvascular endothelial cells was regulated by VEGF. The importance of VEGF produced by ALL cells in mediating leukemia-cell entry into the CNS and leptomeningeal infiltration was further demonstrated by specific reduction of CNS leukemia on in vivo VEGF capture by the anti-VEGF antibody bevacizumab. Thus, we identified a mechanism of ALL-cell entry into the CNS, which by targeting VEGF signaling may serve as a novel strategy to control CNS leukemia in patients, replacing conventional CNS-toxic treatment. | ||
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| contents | In acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is a major clinical concern. Despite nondetectable CNS leukemia in many cases, prophylactic CNS-directed conventional intrathecal chemotherapy is required for relapse-free survival, indicating subclinical CNS manifestation in most patients. However, CNS-directed therapy is associated with long-term sequelae, including neurocognitive deficits and secondary neoplasms. Therefore, molecular mechanisms and pathways mediating leukemia-cell entry into the CNS need to be understood to identify targets for prophylactic and therapeutic interventions and develop alternative CNS-directed treatment strategies. In this study, we analyzed leukemia-cell entry into the CNS using a primograft ALL mouse model. We found that primary ALL cells transplanted onto nonobese diabetic/severe combined immunodeficiency mice faithfully recapitulated clinical and pathological features of meningeal infiltration seen in patients with ALL. ALL cells that had entered the CNS and were infiltrating the meninges were characterized by high expression of vascular endothelial growth factor A (VEGF). Although cellular viability, growth, proliferation, and survival of ALL cells were found to be independent of VEGF, transendothelial migration through CNS microvascular endothelial cells was regulated by VEGF. The importance of VEGF produced by ALL cells in mediating leukemia-cell entry into the CNS and leptomeningeal infiltration was further demonstrated by specific reduction of CNS leukemia on in vivo VEGF capture by the anti-VEGF antibody bevacizumab. Thus, we identified a mechanism of ALL-cell entry into the CNS, which by targeting VEGF signaling may serve as a novel strategy to control CNS leukemia in patients, replacing conventional CNS-toxic treatment. |
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| spelling | Münch, Vera VerfasserIn (DE-588)1147855854 (DE-627)1007234555 (DE-576)496072528 aut, Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor Vera Münch, Luca Trentin, Julia Herzig, Salih Demir, Felix Seyfried, Johann M. Kraus, Hans A. Kestler, Rolf Köhler, Thomas F. E. Barth, Geertruy te Kronnie, Klaus-Michael Debatin, and Lüder H. Meyer, 26 May 2017, 12, Text txt rdacontent, Computermedien c rdamedia, Online-Ressource cr rdacarrier, Gesehen am 21.08.2018, In acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is a major clinical concern. Despite nondetectable CNS leukemia in many cases, prophylactic CNS-directed conventional intrathecal chemotherapy is required for relapse-free survival, indicating subclinical CNS manifestation in most patients. However, CNS-directed therapy is associated with long-term sequelae, including neurocognitive deficits and secondary neoplasms. Therefore, molecular mechanisms and pathways mediating leukemia-cell entry into the CNS need to be understood to identify targets for prophylactic and therapeutic interventions and develop alternative CNS-directed treatment strategies. In this study, we analyzed leukemia-cell entry into the CNS using a primograft ALL mouse model. We found that primary ALL cells transplanted onto nonobese diabetic/severe combined immunodeficiency mice faithfully recapitulated clinical and pathological features of meningeal infiltration seen in patients with ALL. ALL cells that had entered the CNS and were infiltrating the meninges were characterized by high expression of vascular endothelial growth factor A (VEGF). Although cellular viability, growth, proliferation, and survival of ALL cells were found to be independent of VEGF, transendothelial migration through CNS microvascular endothelial cells was regulated by VEGF. The importance of VEGF produced by ALL cells in mediating leukemia-cell entry into the CNS and leptomeningeal infiltration was further demonstrated by specific reduction of CNS leukemia on in vivo VEGF capture by the anti-VEGF antibody bevacizumab. Thus, we identified a mechanism of ALL-cell entry into the CNS, which by targeting VEGF signaling may serve as a novel strategy to control CNS leukemia in patients, replacing conventional CNS-toxic treatment., Trentin, Luca VerfasserIn (DE-588)1165088940 (DE-627)1029638349 (DE-576)510242693 aut, Herzig, Julia Katharina VerfasserIn (DE-588)1158601581 (DE-627)1020587326 (DE-576)50424017X aut, Köhler, Rolf 1966- VerfasserIn (DE-588)12289751X (DE-627)082221545 (DE-576)293468427 aut, Enthalten in Blood Washington, DC : American Society of Hematology, 1946 130(2017), 5, Seite 643-654 Online-Ressource (DE-627)266886647 (DE-600)1468538-3 (DE-576)075961938 1528-0020 nnns, volume:130 year:2017 number:5 pages:643-654 extent:12, http://dx.doi.org/10.1182/blood-2017-03-769315 Verlag Resolving-System kostenfrei Volltext, http://www.bloodjournal.org/content/130/5/643 Verlag kostenfrei Volltext, http://dx.doi.org/10.1182/blood-2017-03-769315 LFER, LFER 2018-09-13T00:00:00Z |
| spellingShingle | Münch, Vera, Trentin, Luca, Herzig, Julia Katharina, Köhler, Rolf, Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor, In acute lymphoblastic leukemia (ALL), central nervous system (CNS) involvement is a major clinical concern. Despite nondetectable CNS leukemia in many cases, prophylactic CNS-directed conventional intrathecal chemotherapy is required for relapse-free survival, indicating subclinical CNS manifestation in most patients. However, CNS-directed therapy is associated with long-term sequelae, including neurocognitive deficits and secondary neoplasms. Therefore, molecular mechanisms and pathways mediating leukemia-cell entry into the CNS need to be understood to identify targets for prophylactic and therapeutic interventions and develop alternative CNS-directed treatment strategies. In this study, we analyzed leukemia-cell entry into the CNS using a primograft ALL mouse model. We found that primary ALL cells transplanted onto nonobese diabetic/severe combined immunodeficiency mice faithfully recapitulated clinical and pathological features of meningeal infiltration seen in patients with ALL. ALL cells that had entered the CNS and were infiltrating the meninges were characterized by high expression of vascular endothelial growth factor A (VEGF). Although cellular viability, growth, proliferation, and survival of ALL cells were found to be independent of VEGF, transendothelial migration through CNS microvascular endothelial cells was regulated by VEGF. The importance of VEGF produced by ALL cells in mediating leukemia-cell entry into the CNS and leptomeningeal infiltration was further demonstrated by specific reduction of CNS leukemia on in vivo VEGF capture by the anti-VEGF antibody bevacizumab. Thus, we identified a mechanism of ALL-cell entry into the CNS, which by targeting VEGF signaling may serve as a novel strategy to control CNS leukemia in patients, replacing conventional CNS-toxic treatment. |
| swb_id_str | 510242707 |
| title | Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor |
| title_auth | Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor |
| title_full | Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor Vera Münch, Luca Trentin, Julia Herzig, Salih Demir, Felix Seyfried, Johann M. Kraus, Hans A. Kestler, Rolf Köhler, Thomas F. E. Barth, Geertruy te Kronnie, Klaus-Michael Debatin, and Lüder H. Meyer |
| title_fullStr | Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor Vera Münch, Luca Trentin, Julia Herzig, Salih Demir, Felix Seyfried, Johann M. Kraus, Hans A. Kestler, Rolf Köhler, Thomas F. E. Barth, Geertruy te Kronnie, Klaus-Michael Debatin, and Lüder H. Meyer |
| title_full_unstemmed | Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor Vera Münch, Luca Trentin, Julia Herzig, Salih Demir, Felix Seyfried, Johann M. Kraus, Hans A. Kestler, Rolf Köhler, Thomas F. E. Barth, Geertruy te Kronnie, Klaus-Michael Debatin, and Lüder H. Meyer |
| title_in_hierarchy | Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor / Vera Münch, Luca Trentin, Julia Herzig, Salih Demir, Felix Seyfried, Johann M. Kraus, Hans A. Kestler, Rolf Köhler, Thomas F. E. Barth, Geertruy te Kronnie, Klaus-Michael Debatin, and Lüder H. Meyer, |
| title_short | Central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor |
| title_sort | central nervous system involvement in acute lymphoblastic leukemia is mediated by vascular endothelial growth factor |
| url | http://dx.doi.org/10.1182/blood-2017-03-769315, http://www.bloodjournal.org/content/130/5/643 |