Targeting Heterochromatin Eliminates Chronic Myelomonocytic Leukemia Malignant Stem Cells Through Reactivation of Retroelements and Innate Immune pathways

• DOI: 10.1101/2024.02.02.578583
• Publication Date: 2024-02-03T03:15:15Z
• Authors: Donia Hidaoui; Audrey Porquet; Rabie Chelbi; Mathieu Bohm; Aikaterini Polyzou; Vincent Alcazer; Stéphane Depil; Aygun Imanci; Margot Morabito; Aline Renneville; Dorothée Sélimogl...; Sylvain Thépot; Raphael Itzykson; Lucie Laplane; Nathalie Droin; Eirini Trompouki; Emilie Elvira-Mat...; Eric Solary; Françoise Porteu
• Keywords: PRC2

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 malignant clone. Hematopoietic stem cell (HSC) aging involves heterochromatin reorganization, evidenced by alterations in histone marks H3K9me2 and H3K9me3. These repressive together with methylation essential suppressing transposable elements (TEs). In solid cancers, antitumor efficacy of HMAs derepression TEs, mimicking state viral infection. this study, we demonstrate significant disorganization CMML HSCs progenitors (HSPCs) characterized an increase mark H3K9me2, mainly at level repression immune age-associated transcripts. Combining G9A/GLP methyltransferase inhibitors reactivates these pathways, selectively targeting mutated cells while preserving wild-type HSCs, thus offering new avenues malignancy.