Targeting heterochromatin eliminates chronic myelomonocytic leukemia malignant stem cells through reactivation of retroelements and immune pathways
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.
Authors
- Françoise Porteu (ORCID: https://orcid.org/0000-0002-2403-4163)
- Raphaël Itzykson (ORCID: https://orcid.org/0000-0003-2139-6262)
- Sylvain Thépot (ORCID: https://orcid.org/0000-0003-3492-2778)
- Vincent Alcazer (ORCID: https://orcid.org/0000-0003-1843-6286)
- Eirini Trompouki (ORCID: https://orcid.org/0000-0002-7242-8810)
- Éric Solary (ORCID: https://orcid.org/0000-0002-8629-1341)
- Rabie Chelbi (ORCID: https://orcid.org/0000-0001-5994-328X)
- Lucie Laplane (ORCID: https://orcid.org/0000-0003-0185-3323)
- Donia Hidaoui (ORCID: https://orcid.org/0000-0002-9350-339X)
- Mathieu Bohm (ORCID: https://orcid.org/0000-0001-5090-1569)
- Aline Renneville (ORCID: https://orcid.org/0000-0003-0805-9640)
- Stéphane Depil (ORCID: https://orcid.org/0000-0001-6011-3945)
- Aygun Imanci
- Margot Morabito
- Emilie Elvira‐Matelot (ORCID: https://orcid.org/0000-0002-4017-6436)
- Nathalie Droin (ORCID: https://orcid.org/0000-0002-6099-5324)
- Dorothée Selimoglu‐Buet (ORCID: https://orcid.org/0000-0002-3565-2709)
- Aikaterini Polyzou
- Audrey Porquet
Institutions
- Université Claude Bernard Lyon 1 (FR)
- Centre National de la Recherche Scientifique (FR)
- Inserm (FR)
- Université Côte d'Azur (FR)
- Université Paris Cité (FR)
- Université Paris-Saclay (FR)
- Institut Gustave Roussy (FR)
- Assistance Publique – Hôpitaux de Paris (FR)
- Hospices Civils de Lyon (FR)
- Centre Léon Bérard (FR)
- Hôpital Lyon Sud (FR)
- Institut d'Histoire et de Philosophie des Sciences et des Techniques (FR)
- Institut de Recherche sur le Cancer et le Vieillissement de Nice (FR)
- Centre de Recherche en Cancérologie de Lyon (FR)
- Hôpital Saint-Louis (FR)
- Centre International de Recherche en Infectiologie (FR)
- Université d'Angers (FR)
- Université Paris 1 Panthéon-Sorbonne (FR)
Publication Details
- Journal
- Communications Biology
- Published
- 2024-11-22
- DOI
- https://doi.org/10.1038/s42003-024-07214-1
- Citations
- 8
- Primary Topic
- Acute Myeloid Leukemia Research
- Type
- article
- Field-Weighted Citation Impact
- 3.64
Funders
- Institut National de la Santé et de la Recherche Médicale
- Institut National Du Cancer
- Institut Gustave-Roussy