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

Overview

Journal Commun Biol

Specialty Biology

Date 2024 Nov 23

PMID 39578583

Authors

Donia Hidaoui

Audrey Porquet

Rabie Chelbi

Mathieu Bohm

Aikaterini Polyzou

Vincent Alcazer

Stephane Depil

Aygun Imanci

Margot Morabito

Aline Renneville

Dorothee Selimoglu-Buet

Sylvain Thepot

Raphael Itzykson

Lucie Laplane

Nathalie Droin

Eirini Trompouki

Emilie Elvira-Matelot

Eric Solary

Francoise Porteu

Affiliations

Soon will be listed here.

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.

Citing Articles

Endogenous retroelements in hematological malignancies: From epigenetic dysregulation to therapeutic targeting.

Chour M, Porteu F, Depil S, Alcazer V Am J Hematol. 2024; 100(1):116-130.

PMID: 39387681 PMC: 11625990. DOI: 10.1002/ajh.27501.

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