Cargando…
The mitochondrial anti-apoptotic dependencies of hematologic malignancies: from disease biology to advances in precision medicine
Mitochondria are critical organelles in the regulation of intrinsic apoptosis. As a general feature of blood cancers, different antiapoptotic members of the BCL-2 protein family localize at the outer mitochondrial membrane to sequester variable amounts of proapoptotic activators, and hence protect c...
Autores principales: | , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Fondazione Ferrata Storti
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968907/ https://www.ncbi.nlm.nih.gov/pubmed/35045693 http://dx.doi.org/10.3324/haematol.2021.280201 |
_version_ | 1784679144807727104 |
---|---|
author | Ferrarini, Isacco Rigo, Antonella Visco, Carlo |
author_facet | Ferrarini, Isacco Rigo, Antonella Visco, Carlo |
author_sort | Ferrarini, Isacco |
collection | PubMed |
description | Mitochondria are critical organelles in the regulation of intrinsic apoptosis. As a general feature of blood cancers, different antiapoptotic members of the BCL-2 protein family localize at the outer mitochondrial membrane to sequester variable amounts of proapoptotic activators, and hence protect cancer cells from death induction. However, the impact of distinct anti-apoptotic members on apoptosis prevention, a concept termed anti-apoptotic dependence, differs remarkably across disease entities. Over the last two decades, several genetic and functional methodologies have been established to uncover the anti-apoptotic dependencies of the majority of blood cancers, inspiring the development of a new class of small molecules called BH3 mimetics. In this review, we highlight the rationale of targeting mitochondrial apoptosis in hematology, and provide a comprehensive map of the anti-apoptotic dependencies that are currently guiding novel therapeutic strategies. Cell-extrinsic and -intrinsic mechanisms conferring resistance to BH3 mimetics are also examined, with insights on potential strategies to overcome them. Finally, we discuss how the field of mitochondrial apoptosis might be complemented with other dimensions of precision medicine for more successful treatment of ‘highly complex’ hematologic malignancies. |
format | Online Article Text |
id | pubmed-8968907 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Fondazione Ferrata Storti |
record_format | MEDLINE/PubMed |
spelling | pubmed-89689072022-04-11 The mitochondrial anti-apoptotic dependencies of hematologic malignancies: from disease biology to advances in precision medicine Ferrarini, Isacco Rigo, Antonella Visco, Carlo Haematologica Review Article Mitochondria are critical organelles in the regulation of intrinsic apoptosis. As a general feature of blood cancers, different antiapoptotic members of the BCL-2 protein family localize at the outer mitochondrial membrane to sequester variable amounts of proapoptotic activators, and hence protect cancer cells from death induction. However, the impact of distinct anti-apoptotic members on apoptosis prevention, a concept termed anti-apoptotic dependence, differs remarkably across disease entities. Over the last two decades, several genetic and functional methodologies have been established to uncover the anti-apoptotic dependencies of the majority of blood cancers, inspiring the development of a new class of small molecules called BH3 mimetics. In this review, we highlight the rationale of targeting mitochondrial apoptosis in hematology, and provide a comprehensive map of the anti-apoptotic dependencies that are currently guiding novel therapeutic strategies. Cell-extrinsic and -intrinsic mechanisms conferring resistance to BH3 mimetics are also examined, with insights on potential strategies to overcome them. Finally, we discuss how the field of mitochondrial apoptosis might be complemented with other dimensions of precision medicine for more successful treatment of ‘highly complex’ hematologic malignancies. Fondazione Ferrata Storti 2022-01-20 /pmc/articles/PMC8968907/ /pubmed/35045693 http://dx.doi.org/10.3324/haematol.2021.280201 Text en Copyright© 2022 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. |
spellingShingle | Review Article Ferrarini, Isacco Rigo, Antonella Visco, Carlo The mitochondrial anti-apoptotic dependencies of hematologic malignancies: from disease biology to advances in precision medicine |
title | The mitochondrial anti-apoptotic dependencies of hematologic malignancies: from disease biology to advances in precision medicine |
title_full | The mitochondrial anti-apoptotic dependencies of hematologic malignancies: from disease biology to advances in precision medicine |
title_fullStr | The mitochondrial anti-apoptotic dependencies of hematologic malignancies: from disease biology to advances in precision medicine |
title_full_unstemmed | The mitochondrial anti-apoptotic dependencies of hematologic malignancies: from disease biology to advances in precision medicine |
title_short | The mitochondrial anti-apoptotic dependencies of hematologic malignancies: from disease biology to advances in precision medicine |
title_sort | mitochondrial anti-apoptotic dependencies of hematologic malignancies: from disease biology to advances in precision medicine |
topic | Review Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8968907/ https://www.ncbi.nlm.nih.gov/pubmed/35045693 http://dx.doi.org/10.3324/haematol.2021.280201 |
work_keys_str_mv | AT ferrariniisacco themitochondrialantiapoptoticdependenciesofhematologicmalignanciesfromdiseasebiologytoadvancesinprecisionmedicine AT rigoantonella themitochondrialantiapoptoticdependenciesofhematologicmalignanciesfromdiseasebiologytoadvancesinprecisionmedicine AT viscocarlo themitochondrialantiapoptoticdependenciesofhematologicmalignanciesfromdiseasebiologytoadvancesinprecisionmedicine AT ferrariniisacco mitochondrialantiapoptoticdependenciesofhematologicmalignanciesfromdiseasebiologytoadvancesinprecisionmedicine AT rigoantonella mitochondrialantiapoptoticdependenciesofhematologicmalignanciesfromdiseasebiologytoadvancesinprecisionmedicine AT viscocarlo mitochondrialantiapoptoticdependenciesofhematologicmalignanciesfromdiseasebiologytoadvancesinprecisionmedicine |