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A self-assembled leucine polymer sensitizes leukemic stem cells to chemotherapy by inhibiting autophagy in acute myeloid leukemia

Chemotherapy is the primary treatment option for acute myeloid leukemia (AML), but leukemic stem cells (LSC) can survive chemotherapy for disease recurrence and refractory. Here, we found that AML cells obtained from relapsed patients had increased autophagy levels than de novo AML cells. Furthermor...

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Autores principales: Xu, Xi, Wang, Jian, Tong, Tong, Zhang, Wenwen, Wang, Jin, Ma, Weiwei, Wang, Shunqing, Zhou, Dunhua, Wu, Jun, Jiang, Linjia, Zhao, Meng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9521229/
https://www.ncbi.nlm.nih.gov/pubmed/35295079
http://dx.doi.org/10.3324/haematol.2021.280290
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author Xu, Xi
Wang, Jian
Tong, Tong
Zhang, Wenwen
Wang, Jin
Ma, Weiwei
Wang, Shunqing
Zhou, Dunhua
Wu, Jun
Jiang, Linjia
Zhao, Meng
author_facet Xu, Xi
Wang, Jian
Tong, Tong
Zhang, Wenwen
Wang, Jin
Ma, Weiwei
Wang, Shunqing
Zhou, Dunhua
Wu, Jun
Jiang, Linjia
Zhao, Meng
author_sort Xu, Xi
collection PubMed
description Chemotherapy is the primary treatment option for acute myeloid leukemia (AML), but leukemic stem cells (LSC) can survive chemotherapy for disease recurrence and refractory. Here, we found that AML cells obtained from relapsed patients had increased autophagy levels than de novo AML cells. Furthermore, doxorubicin (DOX) treatment stimulated autophagy in LSC by repressing the mTOR pathway, and pharmaceutical inhibition of autophagy rendered chemoresistant LSC sensitive to DOX treatment in MLL-AF9 induced murine AML. Moreover, we developed a self-assembled leucine polymer, which activated mTOR to inhibit autophagy in AML cells by releasing leucine. The leucine polymer loaded DOX (Leu-DOX) induced much less autophagy but more robust apoptosis in AML cells than the DOX treatment. Notably, the leucine polymer and Leu-DOX were specifically taken up by AML cells and LSC but not by normal hematopoietic cells and hematopoietic stem/progenitor cells in the bone marrow. Consequently, Leu-DOX efficiently reduced LSC and prolonged the survival of AML mice, with more limited myeloablation and tissue damage side effects than DOX treatment. Overall, we proposed that the newly developed Leu-DOX is an effective autophagy inhibitor and an ideal drug to efficiently eliminate LSC, thus serving as a revolutionary strategy to enhance the chemotherapy efficacy in AML.
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spelling pubmed-95212292022-10-24 A self-assembled leucine polymer sensitizes leukemic stem cells to chemotherapy by inhibiting autophagy in acute myeloid leukemia Xu, Xi Wang, Jian Tong, Tong Zhang, Wenwen Wang, Jin Ma, Weiwei Wang, Shunqing Zhou, Dunhua Wu, Jun Jiang, Linjia Zhao, Meng Haematologica Article - Acute Myeloid Leukemia Chemotherapy is the primary treatment option for acute myeloid leukemia (AML), but leukemic stem cells (LSC) can survive chemotherapy for disease recurrence and refractory. Here, we found that AML cells obtained from relapsed patients had increased autophagy levels than de novo AML cells. Furthermore, doxorubicin (DOX) treatment stimulated autophagy in LSC by repressing the mTOR pathway, and pharmaceutical inhibition of autophagy rendered chemoresistant LSC sensitive to DOX treatment in MLL-AF9 induced murine AML. Moreover, we developed a self-assembled leucine polymer, which activated mTOR to inhibit autophagy in AML cells by releasing leucine. The leucine polymer loaded DOX (Leu-DOX) induced much less autophagy but more robust apoptosis in AML cells than the DOX treatment. Notably, the leucine polymer and Leu-DOX were specifically taken up by AML cells and LSC but not by normal hematopoietic cells and hematopoietic stem/progenitor cells in the bone marrow. Consequently, Leu-DOX efficiently reduced LSC and prolonged the survival of AML mice, with more limited myeloablation and tissue damage side effects than DOX treatment. Overall, we proposed that the newly developed Leu-DOX is an effective autophagy inhibitor and an ideal drug to efficiently eliminate LSC, thus serving as a revolutionary strategy to enhance the chemotherapy efficacy in AML. Fondazione Ferrata Storti 2022-03-17 /pmc/articles/PMC9521229/ /pubmed/35295079 http://dx.doi.org/10.3324/haematol.2021.280290 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 Article - Acute Myeloid Leukemia
Xu, Xi
Wang, Jian
Tong, Tong
Zhang, Wenwen
Wang, Jin
Ma, Weiwei
Wang, Shunqing
Zhou, Dunhua
Wu, Jun
Jiang, Linjia
Zhao, Meng
A self-assembled leucine polymer sensitizes leukemic stem cells to chemotherapy by inhibiting autophagy in acute myeloid leukemia
title A self-assembled leucine polymer sensitizes leukemic stem cells to chemotherapy by inhibiting autophagy in acute myeloid leukemia
title_full A self-assembled leucine polymer sensitizes leukemic stem cells to chemotherapy by inhibiting autophagy in acute myeloid leukemia
title_fullStr A self-assembled leucine polymer sensitizes leukemic stem cells to chemotherapy by inhibiting autophagy in acute myeloid leukemia
title_full_unstemmed A self-assembled leucine polymer sensitizes leukemic stem cells to chemotherapy by inhibiting autophagy in acute myeloid leukemia
title_short A self-assembled leucine polymer sensitizes leukemic stem cells to chemotherapy by inhibiting autophagy in acute myeloid leukemia
title_sort self-assembled leucine polymer sensitizes leukemic stem cells to chemotherapy by inhibiting autophagy in acute myeloid leukemia
topic Article - Acute Myeloid Leukemia
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9521229/
https://www.ncbi.nlm.nih.gov/pubmed/35295079
http://dx.doi.org/10.3324/haematol.2021.280290
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