Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells
Targeting FLT3-ITD in AML using TKI against FLT3 cannot prevent relapse even in the presence of complete remission, suggesting the resistance and/or the persistence of leukemic-initiating cells in the hematopoietic niche. By mimicking the hematopoietic niche condition with cultures at low oxygen con...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-01-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/14/2/453 |
| _version_ | 1797495273906241536 |
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| author | Marine Dupont Mathilde Huart Claire Lauvinerie Audrey Bidet Amélie Valérie Guitart Arnaud Villacreces Isabelle Vigon Vanessa Desplat Ali El Habhab Arnaud Pigneux Zoran Ivanovic Philippe Brunet De la Grange Pierre-Yves Dumas Jean-Max Pasquet |
| author_facet | Marine Dupont Mathilde Huart Claire Lauvinerie Audrey Bidet Amélie Valérie Guitart Arnaud Villacreces Isabelle Vigon Vanessa Desplat Ali El Habhab Arnaud Pigneux Zoran Ivanovic Philippe Brunet De la Grange Pierre-Yves Dumas Jean-Max Pasquet |
| author_sort | Marine Dupont |
| collection | DOAJ |
| description | Targeting FLT3-ITD in AML using TKI against FLT3 cannot prevent relapse even in the presence of complete remission, suggesting the resistance and/or the persistence of leukemic-initiating cells in the hematopoietic niche. By mimicking the hematopoietic niche condition with cultures at low oxygen concentrations, we demonstrate in vitro that FLT3-ITD AML cells decrease their repopulating capacity when Vps34 is inhibited. Ex vivo, AML FLT3-ITD blasts treated with Vps34 inhibitors recovered proliferation more slowly due to an increase an apoptosis. In vivo, mice engrafted with FLT3-ITD AML MV4-11 cells have the invasion of the bone marrow and blood in 2 weeks. After 4 weeks of FLT3 TKI treatment with gilteritinib, the leukemic burden had strongly decreased and deep remission was observed. When treatment was discontinued, mice relapsed rapidly. In contrast, Vps34 inhibition strongly decreased the relapse rate, and even more so in association with mobilization by G-CSF and AMD3100. These results demonstrate that remission offers the therapeutic window for a regimen using Vps34 inhibition combined with mobilization to target persistent leukemic stem cells and thus decrease the relapse rate. |
| first_indexed | 2024-03-10T01:46:28Z |
| format | Article |
| id | doaj.art-b64c2a1d0aaa45b793f9fa0dabde1c19 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T01:46:28Z |
| publishDate | 2022-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-b64c2a1d0aaa45b793f9fa0dabde1c192023-11-23T13:15:15ZengMDPI AGCancers2072-66942022-01-0114245310.3390/cancers14020453Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic CellsMarine Dupont0Mathilde Huart1Claire Lauvinerie2Audrey Bidet3Amélie Valérie Guitart4Arnaud Villacreces5Isabelle Vigon6Vanessa Desplat7Ali El Habhab8Arnaud Pigneux9Zoran Ivanovic10Philippe Brunet De la Grange11Pierre-Yves Dumas12Jean-Max Pasquet13Cellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, FranceCellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, FranceCellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, FranceCellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, FranceCellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, FranceCellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, FranceCellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, FranceCellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, FranceCellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, FranceCellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, FranceCellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, FranceCellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, FranceCellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, FranceCellules Souches Hématopoïétiques Normales et Leucémiques, INSERM U1312 BRIC, Université de Bordeaux, Bat TP 4e étage, 146 rue Léo Saignat, 33076 Bordeaux, FranceTargeting FLT3-ITD in AML using TKI against FLT3 cannot prevent relapse even in the presence of complete remission, suggesting the resistance and/or the persistence of leukemic-initiating cells in the hematopoietic niche. By mimicking the hematopoietic niche condition with cultures at low oxygen concentrations, we demonstrate in vitro that FLT3-ITD AML cells decrease their repopulating capacity when Vps34 is inhibited. Ex vivo, AML FLT3-ITD blasts treated with Vps34 inhibitors recovered proliferation more slowly due to an increase an apoptosis. In vivo, mice engrafted with FLT3-ITD AML MV4-11 cells have the invasion of the bone marrow and blood in 2 weeks. After 4 weeks of FLT3 TKI treatment with gilteritinib, the leukemic burden had strongly decreased and deep remission was observed. When treatment was discontinued, mice relapsed rapidly. In contrast, Vps34 inhibition strongly decreased the relapse rate, and even more so in association with mobilization by G-CSF and AMD3100. These results demonstrate that remission offers the therapeutic window for a regimen using Vps34 inhibition combined with mobilization to target persistent leukemic stem cells and thus decrease the relapse rate.https://www.mdpi.com/2072-6694/14/2/453acute myeloid leukemiaFLT3-ITDtyrosine kinase inhibitorspersistenceleukemic initiating cellsautophagy |
| spellingShingle | Marine Dupont Mathilde Huart Claire Lauvinerie Audrey Bidet Amélie Valérie Guitart Arnaud Villacreces Isabelle Vigon Vanessa Desplat Ali El Habhab Arnaud Pigneux Zoran Ivanovic Philippe Brunet De la Grange Pierre-Yves Dumas Jean-Max Pasquet Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells Cancers acute myeloid leukemia FLT3-ITD tyrosine kinase inhibitors persistence leukemic initiating cells autophagy |
| title | Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells |
| title_full | Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells |
| title_fullStr | Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells |
| title_full_unstemmed | Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells |
| title_short | Autophagy Targeting and Hematological Mobilization in FLT3-ITD Acute Myeloid Leukemia Decrease Repopulating Capacity and Relapse by Inducing Apoptosis of Committed Leukemic Cells |
| title_sort | autophagy targeting and hematological mobilization in flt3 itd acute myeloid leukemia decrease repopulating capacity and relapse by inducing apoptosis of committed leukemic cells |
| topic | acute myeloid leukemia FLT3-ITD tyrosine kinase inhibitors persistence leukemic initiating cells autophagy |
| url | https://www.mdpi.com/2072-6694/14/2/453 |
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