Heterogeneity in leukemia cells that escape drug-induced senescence-like state
Abstract Erythropoietin (EPO) suppresses drug-induced apoptosis in EPO-receptor-positive leukemia cells and allows cells to persist after drug treatment by promoting cellular senescence. Importantly a small proportion of senescent cells can re-enter the cell cycle and resume proliferation after drug...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-08-01
|
| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-06015-4 |
| _version_ | 1797752608998293504 |
|---|---|
| author | David Miller Kyra Kerkhofs Farnoosh Abbas-Aghababazadeh Sahib Singh Madahar Mark D. Minden Josée Hébert Benjamin Haibe-Kains Mark A. Bayfield Samuel Benchimol |
| author_facet | David Miller Kyra Kerkhofs Farnoosh Abbas-Aghababazadeh Sahib Singh Madahar Mark D. Minden Josée Hébert Benjamin Haibe-Kains Mark A. Bayfield Samuel Benchimol |
| author_sort | David Miller |
| collection | DOAJ |
| description | Abstract Erythropoietin (EPO) suppresses drug-induced apoptosis in EPO-receptor-positive leukemia cells and allows cells to persist after drug treatment by promoting cellular senescence. Importantly a small proportion of senescent cells can re-enter the cell cycle and resume proliferation after drug treatment, resulting in disease recurrence/persistence. Using a single-cell assay to track individual cells that exit a drug-induced senescence-like state, we show that cells exhibit asynchronous exit from a senescent-like state, and display different rates of proliferation. Escaped cells retain sensitivity to drug treatment, but display inter-clonal variability. We also find heterogeneity in gene expression with some of the escaped clones retaining senescence-associated gene expression. Senescent leukemia cells exhibit changes in gene expression that affect metabolism and senescence-associated secretory phenotype (SASP)-related genes. Herein, we generate a senescence gene signature and show that this signature is a prognostic marker of worse overall survival in AML and multiple other cancers. A portion of senescent leukemia cells depend on lysosome activity; chloroquine, an inhibitor of lysosome activity, promotes senolysis of some senescent leukemia cells. Our study indicates that the serious risks associated with the use of erythropoietin-stimulating agents (ESAs) in anemic cancer patients may be attributed to their ability to promote drug-tolerant cancer cells through the senescence program. |
| first_indexed | 2024-03-12T17:05:51Z |
| format | Article |
| id | doaj.art-394704a1b29e49fa9d8a6266ec257a51 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-12T17:05:51Z |
| publishDate | 2023-08-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-394704a1b29e49fa9d8a6266ec257a512023-08-06T11:26:05ZengNature Publishing GroupCell Death and Disease2041-48892023-08-0114811510.1038/s41419-023-06015-4Heterogeneity in leukemia cells that escape drug-induced senescence-like stateDavid Miller0Kyra Kerkhofs1Farnoosh Abbas-Aghababazadeh2Sahib Singh Madahar3Mark D. Minden4Josée Hébert5Benjamin Haibe-Kains6Mark A. Bayfield7Samuel Benchimol8Department of Biology, York UniversityDepartment of Biology, York UniversityPrincess Margaret Cancer Centre, University Health Network and University of TorontoDepartment of Biology, York UniversityPrincess Margaret Cancer Centre, University Health Network and University of TorontoDivision of Hematology-Oncology, Maisonneuve-Rosemont Hospital and Department of Medicine, Université de MontréalPrincess Margaret Cancer Centre, University Health Network and University of TorontoDepartment of Biology, York UniversityDepartment of Biology, York UniversityAbstract Erythropoietin (EPO) suppresses drug-induced apoptosis in EPO-receptor-positive leukemia cells and allows cells to persist after drug treatment by promoting cellular senescence. Importantly a small proportion of senescent cells can re-enter the cell cycle and resume proliferation after drug treatment, resulting in disease recurrence/persistence. Using a single-cell assay to track individual cells that exit a drug-induced senescence-like state, we show that cells exhibit asynchronous exit from a senescent-like state, and display different rates of proliferation. Escaped cells retain sensitivity to drug treatment, but display inter-clonal variability. We also find heterogeneity in gene expression with some of the escaped clones retaining senescence-associated gene expression. Senescent leukemia cells exhibit changes in gene expression that affect metabolism and senescence-associated secretory phenotype (SASP)-related genes. Herein, we generate a senescence gene signature and show that this signature is a prognostic marker of worse overall survival in AML and multiple other cancers. A portion of senescent leukemia cells depend on lysosome activity; chloroquine, an inhibitor of lysosome activity, promotes senolysis of some senescent leukemia cells. Our study indicates that the serious risks associated with the use of erythropoietin-stimulating agents (ESAs) in anemic cancer patients may be attributed to their ability to promote drug-tolerant cancer cells through the senescence program.https://doi.org/10.1038/s41419-023-06015-4 |
| spellingShingle | David Miller Kyra Kerkhofs Farnoosh Abbas-Aghababazadeh Sahib Singh Madahar Mark D. Minden Josée Hébert Benjamin Haibe-Kains Mark A. Bayfield Samuel Benchimol Heterogeneity in leukemia cells that escape drug-induced senescence-like state Cell Death and Disease |
| title | Heterogeneity in leukemia cells that escape drug-induced senescence-like state |
| title_full | Heterogeneity in leukemia cells that escape drug-induced senescence-like state |
| title_fullStr | Heterogeneity in leukemia cells that escape drug-induced senescence-like state |
| title_full_unstemmed | Heterogeneity in leukemia cells that escape drug-induced senescence-like state |
| title_short | Heterogeneity in leukemia cells that escape drug-induced senescence-like state |
| title_sort | heterogeneity in leukemia cells that escape drug induced senescence like state |
| url | https://doi.org/10.1038/s41419-023-06015-4 |
| work_keys_str_mv | AT davidmiller heterogeneityinleukemiacellsthatescapedruginducedsenescencelikestate AT kyrakerkhofs heterogeneityinleukemiacellsthatescapedruginducedsenescencelikestate AT farnooshabbasaghababazadeh heterogeneityinleukemiacellsthatescapedruginducedsenescencelikestate AT sahibsinghmadahar heterogeneityinleukemiacellsthatescapedruginducedsenescencelikestate AT markdminden heterogeneityinleukemiacellsthatescapedruginducedsenescencelikestate AT joseehebert heterogeneityinleukemiacellsthatescapedruginducedsenescencelikestate AT benjaminhaibekains heterogeneityinleukemiacellsthatescapedruginducedsenescencelikestate AT markabayfield heterogeneityinleukemiacellsthatescapedruginducedsenescencelikestate AT samuelbenchimol heterogeneityinleukemiacellsthatescapedruginducedsenescencelikestate |