Acute myeloid leukemia drug tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity, that also increases their sensitivity to immune cell killing
Resistance to chemotherapy remains a major hurdle to the cure of Acute Myeloid Leukemia (AML) patients. Recent studies indicate a minority of malignant cells, termed drug-tolerant persisters (DTPs), stochastically upregulate stress pathways to evade cell death upon acute exposure to chemotherapy wi...
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| Format: | Article |
| Language: | English |
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Ferrata Storti Foundation
2024-11-01
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| Series: | Haematologica |
| Online Access: | https://haematologica.org/article/view/11834 |
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| author | Yael Morgenstern JongBok Lee Yoosu Na Brandon Y. Lieng Nicholas S. Ly William D. Gwynne Rose Hurren Li Ma Dakai Ling Marcela Gronda Andrea Arruda Avraham Frisch Tsila Zuckerman Yishai Ofran Mark D. Minden Li Zhang Catherine O’Brien Andrew T. Quaile J. Rafael Montenegro-Burke Aaron D. Schimmer |
| author_facet | Yael Morgenstern JongBok Lee Yoosu Na Brandon Y. Lieng Nicholas S. Ly William D. Gwynne Rose Hurren Li Ma Dakai Ling Marcela Gronda Andrea Arruda Avraham Frisch Tsila Zuckerman Yishai Ofran Mark D. Minden Li Zhang Catherine O’Brien Andrew T. Quaile J. Rafael Montenegro-Burke Aaron D. Schimmer |
| author_sort | Yael Morgenstern |
| collection | DOAJ |
| description |
Resistance to chemotherapy remains a major hurdle to the cure of Acute Myeloid Leukemia (AML) patients. Recent studies indicate a minority of malignant cells, termed drug-tolerant persisters (DTPs), stochastically upregulate stress pathways to evade cell death upon acute exposure to chemotherapy without acquiring new genetic mutations. This chemoresistant state is transient and the cells return to baseline after removal of chemotherapy. Yet, the mechanisms employed by DTPs to resist chemotherapy are not well understood and it is largely unknown whether these mechanisms are also seen in patients receiving chemotherapy. Here, we used leukemia cell lines, primary AML patient samples and samples from patients with AML receiving systemic chemotherapy to study the DTP state. We demonstrated that a subset of AML cells transiently increases membrane rigidity to resist killing due to acute exposure to Daunorubicin and Ara-C. Upon removal of the chemotherapy, membrane rigidity returned to baseline and the cells regained chemosensitivity. Although resistant to chemotherapy, the increased membrane rigidity, rendered AML cells more susceptible to T-cell mediated killing. Thus, we identified a novel mechanism by which DTP leukemic cells evade chemotherapy and a strategy to eradicate these persistent cells.
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| format | Article |
| id | doaj-art-2ba74678957f4975aef05eb724f03ebc |
| institution | OA Journals |
| issn | 0390-6078 1592-8721 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Ferrata Storti Foundation |
| record_format | Article |
| series | Haematologica |
| spelling | doaj-art-2ba74678957f4975aef05eb724f03ebc2025-08-20T02:32:42ZengFerrata Storti FoundationHaematologica0390-60781592-87212024-11-01999110.3324/haematol.2024.286018Acute myeloid leukemia drug tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity, that also increases their sensitivity to immune cell killingYael Morgenstern0JongBok Lee1Yoosu Na2Brandon Y. Lieng3Nicholas S. Ly4William D. Gwynne5Rose Hurren6Li Ma7Dakai Ling8Marcela Gronda9Andrea Arruda10Avraham Frisch11Tsila Zuckerman12Yishai Ofran13Mark D. Minden14Li Zhang15Catherine O’Brien16Andrew T. Quaile17J. Rafael Montenegro-Burke18Aaron D. Schimmer19Princess Margaret Cancer Centre, University Health Network, TorontoToronto General Hospital Research Institute, University Health Network, TorontoToronto General Hospital Research Institute, University Health Network, TorontoTerrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, TorontoTerrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, TorontoTerrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, TorontoPrincess Margaret Cancer Centre, University Health Network, TorontoPrincess Margaret Cancer Centre, University Health Network, TorontoPrincess Margaret Cancer Centre, University Health Network, TorontoPrincess Margaret Cancer Centre, University Health Network, TorontoPrincess Margaret Cancer Centre, University Health Network, TorontoDepartment of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, IsraelDepartment of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, IsraelHematology and Stem cell transplantation department and the Eisenberg R-D Authority, Shaare Zedek medical center, Hebrew University Jerusalem, IsraelPrincess Margaret Cancer Centre, University Health Network, TorontoToronto General Hospital Research Institute, University Health Network, TorontoPrincess Margaret Cancer Centre, University Health Network, TorontoTerrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, TorontoTerrence Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, TorontoPrincess Margaret Cancer Centre, University Health Network, Toronto Resistance to chemotherapy remains a major hurdle to the cure of Acute Myeloid Leukemia (AML) patients. Recent studies indicate a minority of malignant cells, termed drug-tolerant persisters (DTPs), stochastically upregulate stress pathways to evade cell death upon acute exposure to chemotherapy without acquiring new genetic mutations. This chemoresistant state is transient and the cells return to baseline after removal of chemotherapy. Yet, the mechanisms employed by DTPs to resist chemotherapy are not well understood and it is largely unknown whether these mechanisms are also seen in patients receiving chemotherapy. Here, we used leukemia cell lines, primary AML patient samples and samples from patients with AML receiving systemic chemotherapy to study the DTP state. We demonstrated that a subset of AML cells transiently increases membrane rigidity to resist killing due to acute exposure to Daunorubicin and Ara-C. Upon removal of the chemotherapy, membrane rigidity returned to baseline and the cells regained chemosensitivity. Although resistant to chemotherapy, the increased membrane rigidity, rendered AML cells more susceptible to T-cell mediated killing. Thus, we identified a novel mechanism by which DTP leukemic cells evade chemotherapy and a strategy to eradicate these persistent cells. https://haematologica.org/article/view/11834 |
| spellingShingle | Yael Morgenstern JongBok Lee Yoosu Na Brandon Y. Lieng Nicholas S. Ly William D. Gwynne Rose Hurren Li Ma Dakai Ling Marcela Gronda Andrea Arruda Avraham Frisch Tsila Zuckerman Yishai Ofran Mark D. Minden Li Zhang Catherine O’Brien Andrew T. Quaile J. Rafael Montenegro-Burke Aaron D. Schimmer Acute myeloid leukemia drug tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity, that also increases their sensitivity to immune cell killing Haematologica |
| title | Acute myeloid leukemia drug tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity, that also increases their sensitivity to immune cell killing |
| title_full | Acute myeloid leukemia drug tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity, that also increases their sensitivity to immune cell killing |
| title_fullStr | Acute myeloid leukemia drug tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity, that also increases their sensitivity to immune cell killing |
| title_full_unstemmed | Acute myeloid leukemia drug tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity, that also increases their sensitivity to immune cell killing |
| title_short | Acute myeloid leukemia drug tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity, that also increases their sensitivity to immune cell killing |
| title_sort | acute myeloid leukemia drug tolerant persister cells survive chemotherapy by transiently increasing plasma membrane rigidity that also increases their sensitivity to immune cell killing |
| url | https://haematologica.org/article/view/11834 |
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