Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways

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

doi:10.1038/s42003-024-07214-1

Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways

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

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Résumé

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.

langue originale	Anglais
Numéro d'article	1555
journal	Communications Biology
Volume	7
Numéro de publication	1
Les DOIs	https://doi.org/10.1038/s42003-024-07214-1
état	Publié - 1 déc. 2024

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10.1038/s42003-024-07214-1

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Hidaoui, D., Porquet, A., Chelbi, R., Bohm, M., Polyzou, A., Alcazer, V., Depil, S., Imanci, A., Morabito, M., Renneville, A., Selimoglu-Buet, D., Thépot, S., Itzykson, R., Laplane, L., Droin, N., Trompouki, E., Elvira-Matelot, E., Solary, E., & Porteu, F. (2024). Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways. Communications Biology, 7(1), Article 1555. https://doi.org/10.1038/s42003-024-07214-1

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title = "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 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.",

author = "Donia Hidaoui and Audrey Porquet and Rabie Chelbi and Mathieu Bohm and Aikaterini Polyzou and Vincent Alcazer and St{\'e}phane Depil and Aygun Imanci and Margot Morabito and Aline Renneville and Doroth{\'e}e Selimoglu-Buet and Sylvain Th{\'e}pot and Raphael Itzykson and Lucie Laplane and Nathalie Droin and Eirini Trompouki and Emilie Elvira-Matelot and Eric Solary and Fran{\c c}oise Porteu",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

month = dec,

day = "1",

doi = "10.1038/s42003-024-07214-1",

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Hidaoui, D, Porquet, A, Chelbi, R, Bohm, M, Polyzou, A, Alcazer, V, Depil, S, Imanci, A, Morabito, M, Renneville, A, Selimoglu-Buet, D, Thépot, S, Itzykson, R, Laplane, L, Droin, N, Trompouki, E, Elvira-Matelot, E, Solary, E & Porteu, F 2024, 'Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways', Communications Biology, VOL. 7, Numéro 1, 1555. https://doi.org/10.1038/s42003-024-07214-1

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T1 - Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways

AU - Hidaoui, Donia

AU - Porquet, Audrey

AU - Chelbi, Rabie

AU - Bohm, Mathieu

AU - Polyzou, Aikaterini

AU - Alcazer, Vincent

AU - Depil, Stéphane

AU - Imanci, Aygun

AU - Morabito, Margot

AU - Renneville, Aline

AU - Selimoglu-Buet, Dorothée

AU - Thépot, Sylvain

AU - Itzykson, Raphael

AU - Laplane, Lucie

AU - Droin, Nathalie

AU - Trompouki, Eirini

AU - Elvira-Matelot, Emilie

AU - Solary, Eric

AU - Porteu, Françoise

PY - 2024/12/1

Y1 - 2024/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s42003-024-07214-1

DO - 10.1038/s42003-024-07214-1

M3 - Article

AN - SCOPUS:85209708041

SN - 2399-3642

VL - 7

JO - Communications Biology

JF - Communications Biology

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