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 a reorganization of heterochromatin, evidenced by alterations in histone marks H3K9me2 and H3K9me3. These repressive marks together with DNA methylation are essential for maintaining genome stability by 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.

Statement of significance

This study reveals significant heterochromatin disorganization in CMML HSPCs, marked by increased repressive H3K9me2 at transposable elements and repression of immune- and aging-related transcripts. Combining DNA hypomethylating agents with H3K9me2 inhibitors selectively targets mutated cells while preserving wild-type cells, offering promising novel therapeutic avenues for this severe myeloid malignancy linked to aging.