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Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma

The BCL-2-specific inhibitor, ABT-199 (venetoclax) has exhibited remarkable clinical activity in nearly all cases of chronic lymphocytic leukemia. In contrast, responses are usually much less in diffuse large B-cell lymphoma (DLBCL), despite high level expression of BCL-2 in over 40% of cases, indic...

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Autores principales: Smith, Victoria M., Dietz, Anna, Henz, Kristina, Bruecher, Daniela, Jackson, Ross, Kowald, Lisa, van Wijk, Sjoerd J.L., Jayne, Sandrine, Macip, Salvador, Fulda, Simone, Dyer, Martin J.S., Vogler, Meike
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ferrata Storti Foundation 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395267/
https://www.ncbi.nlm.nih.gov/pubmed/31601689
http://dx.doi.org/10.3324/haematol.2019.220525
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author Smith, Victoria M.
Dietz, Anna
Henz, Kristina
Bruecher, Daniela
Jackson, Ross
Kowald, Lisa
van Wijk, Sjoerd J.L.
Jayne, Sandrine
Macip, Salvador
Fulda, Simone
Dyer, Martin J.S.
Vogler, Meike
author_facet Smith, Victoria M.
Dietz, Anna
Henz, Kristina
Bruecher, Daniela
Jackson, Ross
Kowald, Lisa
van Wijk, Sjoerd J.L.
Jayne, Sandrine
Macip, Salvador
Fulda, Simone
Dyer, Martin J.S.
Vogler, Meike
author_sort Smith, Victoria M.
collection PubMed
description The BCL-2-specific inhibitor, ABT-199 (venetoclax) has exhibited remarkable clinical activity in nearly all cases of chronic lymphocytic leukemia. In contrast, responses are usually much less in diffuse large B-cell lymphoma (DLBCL), despite high level expression of BCL-2 in over 40% of cases, indicating that co-expression of related anti-apoptotic BCL-2 family proteins may limit the activity of ABT-199. We have investigated the roles of BCL-2 proteins in DLBCL cells using a panel of specific BCL-2 homology 3 (BH3)-mimetics and identified subgroups of these cells that exhibited marked and specific dependency on either BCL-2, BCL-X(L) or MCL-1 for survival. Dependency was associated with selective sequestration of the pro-apoptotic proteins BIM, BAX and BAK by the specific anti-apoptotic BCL-2 protein which was important for cellular survival. Sensitivity to BH3-mimetics was independent of genetic alterations involving the BCL-2 family and only partially correlated with protein expression levels. Treatment with ABT-199 displaced BAX and BIM from BCL-2, subsequently leading to BAK activation and apoptosis. In contrast, apoptosis induced by inhibiting BCL-X(L) with A1331852 was associated with a displacement of both BAX and BAK from BCL-X(L) and occurred independently of BIM. Finally, the MCL-1 inhibitor S63845 induced mainly BAX-dependent apoptosis mediated by a displacement of BAK, BIM and NOXA from MCL-1. In conclusion, our study indicates that in DLBCL, the heterogeneous response to BH3-mimetics is mediated by selective interactions between BAX, BAK and anti-apoptotic BCL-2 proteins.
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spelling pubmed-73952672020-08-07 Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma Smith, Victoria M. Dietz, Anna Henz, Kristina Bruecher, Daniela Jackson, Ross Kowald, Lisa van Wijk, Sjoerd J.L. Jayne, Sandrine Macip, Salvador Fulda, Simone Dyer, Martin J.S. Vogler, Meike Haematologica Articles The BCL-2-specific inhibitor, ABT-199 (venetoclax) has exhibited remarkable clinical activity in nearly all cases of chronic lymphocytic leukemia. In contrast, responses are usually much less in diffuse large B-cell lymphoma (DLBCL), despite high level expression of BCL-2 in over 40% of cases, indicating that co-expression of related anti-apoptotic BCL-2 family proteins may limit the activity of ABT-199. We have investigated the roles of BCL-2 proteins in DLBCL cells using a panel of specific BCL-2 homology 3 (BH3)-mimetics and identified subgroups of these cells that exhibited marked and specific dependency on either BCL-2, BCL-X(L) or MCL-1 for survival. Dependency was associated with selective sequestration of the pro-apoptotic proteins BIM, BAX and BAK by the specific anti-apoptotic BCL-2 protein which was important for cellular survival. Sensitivity to BH3-mimetics was independent of genetic alterations involving the BCL-2 family and only partially correlated with protein expression levels. Treatment with ABT-199 displaced BAX and BIM from BCL-2, subsequently leading to BAK activation and apoptosis. In contrast, apoptosis induced by inhibiting BCL-X(L) with A1331852 was associated with a displacement of both BAX and BAK from BCL-X(L) and occurred independently of BIM. Finally, the MCL-1 inhibitor S63845 induced mainly BAX-dependent apoptosis mediated by a displacement of BAK, BIM and NOXA from MCL-1. In conclusion, our study indicates that in DLBCL, the heterogeneous response to BH3-mimetics is mediated by selective interactions between BAX, BAK and anti-apoptotic BCL-2 proteins. Ferrata Storti Foundation 2020-08 /pmc/articles/PMC7395267/ /pubmed/31601689 http://dx.doi.org/10.3324/haematol.2019.220525 Text en Copyright© 2020 Ferrata Storti Foundation Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions: https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.
spellingShingle Articles
Smith, Victoria M.
Dietz, Anna
Henz, Kristina
Bruecher, Daniela
Jackson, Ross
Kowald, Lisa
van Wijk, Sjoerd J.L.
Jayne, Sandrine
Macip, Salvador
Fulda, Simone
Dyer, Martin J.S.
Vogler, Meike
Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma
title Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma
title_full Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma
title_fullStr Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma
title_full_unstemmed Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma
title_short Specific interactions of BCL-2 family proteins mediate sensitivity to BH3-mimetics in diffuse large B-cell lymphoma
title_sort specific interactions of bcl-2 family proteins mediate sensitivity to bh3-mimetics in diffuse large b-cell lymphoma
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395267/
https://www.ncbi.nlm.nih.gov/pubmed/31601689
http://dx.doi.org/10.3324/haematol.2019.220525
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