Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways
Abstract Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy affecting the elderly, for which therapeutic options are limited. DNA hypomethylating agents (HMAs) provide transient responses, failing to eradicate the malignant clone. Hematopoietic stem cell (HSC) aging involves heter...
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Nature Portfolio
2024-11-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-024-07214-1 |
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| author | Donia Hidaoui Audrey Porquet Rabie Chelbi Mathieu Bohm Aikaterini Polyzou Vincent Alcazer Stéphane Depil Aygun Imanci Margot Morabito Aline Renneville Dorothée Selimoglu-Buet Sylvain Thépot Raphael Itzykson Lucie Laplane Nathalie Droin Eirini Trompouki Emilie Elvira-Matelot Eric Solary Françoise Porteu |
| author_facet | Donia Hidaoui Audrey Porquet Rabie Chelbi Mathieu Bohm Aikaterini Polyzou Vincent Alcazer Stéphane Depil Aygun Imanci Margot Morabito Aline Renneville Dorothée Selimoglu-Buet Sylvain Thépot Raphael Itzykson Lucie Laplane Nathalie Droin Eirini Trompouki Emilie Elvira-Matelot Eric Solary Françoise Porteu |
| author_sort | Donia Hidaoui |
| collection | DOAJ |
| description | Abstract Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy affecting the elderly, for which therapeutic options are limited. DNA hypomethylating agents (HMAs) provide transient responses, failing to eradicate the malignant clone. Hematopoietic stem cell (HSC) aging involves heterochromatin reorganization, evidenced by alterations in histone marks H3K9me2 and H3K9me3. These repressive marks together with DNA methylation are essential for suppressing transposable elements (TEs). In solid cancers, the antitumor efficacy of HMAs involves the derepression of TEs, mimicking a state of viral infection. In this study, we demonstrate a significant disorganization of heterochromatin in CMML HSCs and progenitors (HSPCs) characterized by an increase in the repressive mark H3K9me2, mainly at the level of TEs, and a repression of immune and age-associated transcripts. Combining HMAs with G9A/GLP H3K9me2 methyltransferase inhibitors reactivates these pathways, selectively targeting mutated cells while preserving wild-type HSCs, thus offering new therapeutic avenues for this severe myeloid malignancy. |
| format | Article |
| id | doaj-art-d0d32ed0a4bf4fa2b5ee6523cd1a587f |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Communications Biology |
| spelling | doaj-art-d0d32ed0a4bf4fa2b5ee6523cd1a587f2024-11-24T12:39:09ZengNature PortfolioCommunications Biology2399-36422024-11-017111810.1038/s42003-024-07214-1Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathwaysDonia Hidaoui0Audrey Porquet1Rabie Chelbi2Mathieu Bohm3Aikaterini Polyzou4Vincent Alcazer5Stéphane Depil6Aygun Imanci7Margot Morabito8Aline Renneville9Dorothée Selimoglu-Buet10Sylvain Thépot11Raphael Itzykson12Lucie Laplane13Nathalie Droin14Eirini Trompouki15Emilie Elvira-Matelot16Eric Solary17Françoise Porteu18INSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-SaclayINSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-SaclayINSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-SaclayINSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-SaclayIRCAN Institute for Research on Cancer and Aging, INSERM U1081, CNRS UMR 7284, Université Côte d’AzurCentre International de Recherche en Infectiologie, INSERM U1111 CNRS UMR530Centre de Recherche en Cancérologie de Lyon, UMR INSERM U1052 CNRS 5286 Université Claude Bernard Lyon 1, Centre Léon BérardINSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-SaclayINSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-SaclayINSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-SaclayINSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-SaclayClinical Hematology Department, University HospitalUniversité Paris Cité, Génomes, Biologie Cellulaire et Thérapeutique U944, INSERM, CNRSINSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-SaclayINSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-SaclayIRCAN Institute for Research on Cancer and Aging, INSERM U1081, CNRS UMR 7284, Université Côte d’AzurINSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-SaclayINSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-SaclayINSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-SaclayAbstract Chronic myelomonocytic leukemia (CMML) is a severe myeloid malignancy affecting the elderly, for which therapeutic options are limited. DNA hypomethylating agents (HMAs) provide transient responses, failing to eradicate the malignant clone. Hematopoietic stem cell (HSC) aging involves heterochromatin reorganization, evidenced by alterations in histone marks H3K9me2 and H3K9me3. These repressive marks together with DNA methylation are essential for suppressing transposable elements (TEs). In solid cancers, the antitumor efficacy of HMAs involves the derepression of TEs, mimicking a state of viral infection. In this study, we demonstrate a significant disorganization of heterochromatin in CMML HSCs and progenitors (HSPCs) characterized by an increase in the repressive mark H3K9me2, mainly at the level of TEs, and a repression of immune and age-associated transcripts. Combining HMAs with G9A/GLP H3K9me2 methyltransferase inhibitors reactivates these pathways, selectively targeting mutated cells while preserving wild-type HSCs, thus offering new therapeutic avenues for this severe myeloid malignancy.https://doi.org/10.1038/s42003-024-07214-1 |
| spellingShingle | Donia Hidaoui Audrey Porquet Rabie Chelbi Mathieu Bohm Aikaterini Polyzou Vincent Alcazer Stéphane Depil Aygun Imanci Margot Morabito Aline Renneville Dorothée Selimoglu-Buet Sylvain Thépot Raphael Itzykson Lucie Laplane Nathalie Droin Eirini Trompouki Emilie Elvira-Matelot Eric Solary Françoise Porteu Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways Communications Biology |
| title | Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways |
| title_full | Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways |
| title_fullStr | Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways |
| title_full_unstemmed | Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways |
| title_short | Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways |
| title_sort | targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways |
| url | https://doi.org/10.1038/s42003-024-07214-1 |
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