Chronic myelomonocytic leukemia (CMML) is a severe myeloid hematological malignancy that primarily affects elderly individuals, with a median age at diagnosis of around 72 years. Arising from a hematopoietic stem cell, this disease combines dysplastic and proliferative features, and its prognosis remains poor, with a median survival generally below three years. The only curative option, allogeneic stem cell transplantation, remains difficult to implement owing to patient age and comorbidities. DNA hypomethylating agents represent a standard treatment for certain forms of the disease, but their responses are consistently transient: they restore a more balanced hematopoiesis through an epigenetic effect without reducing the fraction of mutated cells, and therefore do not eradicate the malignant clone.
Aging of hematopoietic stem cells is accompanied by a reorganization of heterochromatin, marked by changes in the repressive histone marks H3K9me2 and H3K9me3. These marks, together with DNA methylation, play an essential role in maintaining genome stability by repressing transposable elements, including retroelements. When derepressed, these elements can generate double-stranded RNA or cytoplasmic complementary DNA that are perceived as signals of infection, triggering a type I interferon response. It is precisely on this mechanism that part of the antitumor efficacy of hypomethylating agents in solid tumors relies, while their role is less well established in hematological malignancies.
To explore this avenue in CMML, the authors characterized chromatin organization in patient stem and progenitor cells, drawing in particular on chromatin accessibility approaches, RNA sequencing, and mapping of the H3K9me2 mark (CUT&Tag technique). The team reveals a marked disorganization of heterochromatin in CMML stem and progenitor cells compared with aged healthy donors, characterized by an increase in the repressive H3K9me2 mark, primarily at transposable elements, associated with repression of immune and aging-related transcripts.
The study further shows that combining hypomethylating agents with inhibitors of the G9A/GLP methyltransferases, which are responsible for the H3K9me2 mark, allows these signaling pathways to be reactivated. This combination selectively targets mutated cells while sparing normal hematopoietic stem cells. By linking the reactivation of retroelements and immune programs to the specific elimination of malignant stem cells, this work opens new therapeutic perspectives for this hematological malignancy with a severe prognosis.