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BCL-XL expression is essential for human erythropoiesis and engraftment of hematopoietic stem cells
The anti-apoptotic BCL-2 proteins (BCL-2, BCL-XL, MCL-1, A1, BCL-W) counteract apoptotic signals emerging during development and under stress conditions, and are thus essential for the survival of every cell. While the “BCL-2 addiction” of different cell types is well described in mouse models, ther...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944703/ https://www.ncbi.nlm.nih.gov/pubmed/31907357 http://dx.doi.org/10.1038/s41419-019-2203-z |
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author | Afreen, Sehar Bohler, Sheila Müller, Alexandra Demmerath, Eva-Maria Weiss, Julia Miriam Jutzi, Jonas Samuel Schachtrup, Kristina Kunze, Mirjam Erlacher, Miriam |
author_facet | Afreen, Sehar Bohler, Sheila Müller, Alexandra Demmerath, Eva-Maria Weiss, Julia Miriam Jutzi, Jonas Samuel Schachtrup, Kristina Kunze, Mirjam Erlacher, Miriam |
author_sort | Afreen, Sehar |
collection | PubMed |
description | The anti-apoptotic BCL-2 proteins (BCL-2, BCL-XL, MCL-1, A1, BCL-W) counteract apoptotic signals emerging during development and under stress conditions, and are thus essential for the survival of every cell. While the “BCL-2 addiction” of different cell types is well described in mouse models, there is only limited information available on the role of different anti-apoptotic BCL-2 proteins in a given human cell type. Here we characterize the role of BCL-XL for survival and function of human hematopoietic cells, with the aim to predict hematological side effects of novel BCL-XL-inhibiting BH3-mimetics and to identify hematological malignancies potentially responsive to such inhibitors. Earlier clinical studies have shown that the combined BCL-2/BCL-XL/BCL-W inhibitor, Navitoclax (ABT-263) induces severe thrombocytopenia caused by direct platelet demise and counteracted by increased megakaryopoiesis. In contrast, murine studies have reported important contribution of BCL-XL to survival of late erythroid cells and megakaryocytes. Using lentiviral knockdown, we show that the roles of BCL-XL for human hematopoietic cells are much more pronounced than expected from murine data and clinical trials. Efficient genetic or chemical BCL-XL inhibition resulted in significant loss of human erythroid cells beginning from very early stages of erythropoiesis, and in a reduction of megakaryocytes. Most importantly, BCL-XL deficient human hematopoietic stem cells and multipotent progenitors were reduced in numbers, and they showed a severely impaired capacity to engraft in mice during xenotransplantation. BCL-XL deficiency was fully compensated by BCL-2 overexpression, however, loss of its antagonist BIM did not result in any rescue of human erythroid or stem and progenitor cells. We thus conclude that novel and specific BCL-XL inhibitors might be efficient to treat malignancies of erythroid or megakaryocytic origin, such as polycythemia vera, acute erythroid leukemia, essential thrombocytosis or acute megakaryocytic leukemia. At the same time, it can be expected that they will have more severe hematological side effects than Navitoclax. |
format | Online Article Text |
id | pubmed-6944703 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-69447032020-01-07 BCL-XL expression is essential for human erythropoiesis and engraftment of hematopoietic stem cells Afreen, Sehar Bohler, Sheila Müller, Alexandra Demmerath, Eva-Maria Weiss, Julia Miriam Jutzi, Jonas Samuel Schachtrup, Kristina Kunze, Mirjam Erlacher, Miriam Cell Death Dis Article The anti-apoptotic BCL-2 proteins (BCL-2, BCL-XL, MCL-1, A1, BCL-W) counteract apoptotic signals emerging during development and under stress conditions, and are thus essential for the survival of every cell. While the “BCL-2 addiction” of different cell types is well described in mouse models, there is only limited information available on the role of different anti-apoptotic BCL-2 proteins in a given human cell type. Here we characterize the role of BCL-XL for survival and function of human hematopoietic cells, with the aim to predict hematological side effects of novel BCL-XL-inhibiting BH3-mimetics and to identify hematological malignancies potentially responsive to such inhibitors. Earlier clinical studies have shown that the combined BCL-2/BCL-XL/BCL-W inhibitor, Navitoclax (ABT-263) induces severe thrombocytopenia caused by direct platelet demise and counteracted by increased megakaryopoiesis. In contrast, murine studies have reported important contribution of BCL-XL to survival of late erythroid cells and megakaryocytes. Using lentiviral knockdown, we show that the roles of BCL-XL for human hematopoietic cells are much more pronounced than expected from murine data and clinical trials. Efficient genetic or chemical BCL-XL inhibition resulted in significant loss of human erythroid cells beginning from very early stages of erythropoiesis, and in a reduction of megakaryocytes. Most importantly, BCL-XL deficient human hematopoietic stem cells and multipotent progenitors were reduced in numbers, and they showed a severely impaired capacity to engraft in mice during xenotransplantation. BCL-XL deficiency was fully compensated by BCL-2 overexpression, however, loss of its antagonist BIM did not result in any rescue of human erythroid or stem and progenitor cells. We thus conclude that novel and specific BCL-XL inhibitors might be efficient to treat malignancies of erythroid or megakaryocytic origin, such as polycythemia vera, acute erythroid leukemia, essential thrombocytosis or acute megakaryocytic leukemia. At the same time, it can be expected that they will have more severe hematological side effects than Navitoclax. Nature Publishing Group UK 2020-01-06 /pmc/articles/PMC6944703/ /pubmed/31907357 http://dx.doi.org/10.1038/s41419-019-2203-z Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Afreen, Sehar Bohler, Sheila Müller, Alexandra Demmerath, Eva-Maria Weiss, Julia Miriam Jutzi, Jonas Samuel Schachtrup, Kristina Kunze, Mirjam Erlacher, Miriam BCL-XL expression is essential for human erythropoiesis and engraftment of hematopoietic stem cells |
title | BCL-XL expression is essential for human erythropoiesis and engraftment of hematopoietic stem cells |
title_full | BCL-XL expression is essential for human erythropoiesis and engraftment of hematopoietic stem cells |
title_fullStr | BCL-XL expression is essential for human erythropoiesis and engraftment of hematopoietic stem cells |
title_full_unstemmed | BCL-XL expression is essential for human erythropoiesis and engraftment of hematopoietic stem cells |
title_short | BCL-XL expression is essential for human erythropoiesis and engraftment of hematopoietic stem cells |
title_sort | bcl-xl expression is essential for human erythropoiesis and engraftment of hematopoietic stem cells |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6944703/ https://www.ncbi.nlm.nih.gov/pubmed/31907357 http://dx.doi.org/10.1038/s41419-019-2203-z |
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