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

INSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-Saclay, 94805, Villejuif, France.INSERM UMR1287, Gustave Roussy Cancer Center, Université Paris-Saclay, 94805, Villejuif, France. · pubmed

Paper

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.

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Research summary

The paper addresses chronic myelomonocytic leukemia (CMML), a disease prevalent in the elderly, and explores the mechanisms of heterochromatin disorganization and its implications for hematopoietic stem cell aging. While it does not directly target the root causes of aging, it investigates pathways related to cellular aging and potential therapeutic strategies that could improve outcomes in age-related malignancies. The findings contribute to understanding the disease and suggest new therapeutic avenues, but the impact is limited as it primarily focuses on a specific cancer rather than broader aging mechanisms.

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