From DNA marks to RNA control: a new clue to myeloid leukaemia

Acute myeloid leukaemia (AML) is an aggressive blood cancer in which abnormal, immature cells build up in the bone marrow, disrupting the production of healthy blood cells. Now, a new study, led by Dr José Luis Sardina’s group at the Josep Carreras Leukaemia Research Institute (IJC), examines how two systems that help control normal blood cell development are connected: the chemical marks on DNA and the regulation of RNA, which carries instructions for making proteins.

TET2 is one of the genes frequently mutated in AML. It produces a protein that regulates DNA methylation, a type of chemical marking that helps control gene activity without altering the DNA sequence. This is part of a broader system known as epigenetics. Although TET2 plays an important role in blood cell development, how it directs the genetic programmes that guide cell identity is still not fully understood.

Dr Aleksey Lazarenkov is the first author of the investigation, studying cells as they developed into macrophages, a type of immune cell. The team mapped where TET2 acts along the DNA and examined DNA methylation, gene activity and DNA organisation. They identified several gene regulatory regions associated with TET2, including one within the AGO2 gene.

Linking epigenetic regulation to RNA control in blood cell development

The AGO2 gene produces the AGO2 protein, which is involved in RNA interference, a process that helps cells control the fate of RNA molecules, including whether they are broken down or used to make proteins. The researchers found that TET2 binds to regulatory regions within the AGO2 gene, where it helps remove DNA methylation marks and promote AGO2 expression. This reveals how epigenetic regulation can influence the machinery that controls RNA.

Reducing AGO2 levels accelerated the acquisition of macrophage identity and altered processes involved in cell growth, metabolism and inflammatory responses. These findings suggest that AGO2 contributes to the coordination of myeloid cell identity with the cellular programmes that support cell growth, prompting the team to investigate whether leukaemia cells also depend on this protein.

“Interestingly, our findings suggest that AGO2 helps coordinate the acquisition of myeloid cell identity with the programmes that support cell growth. This led us to ask whether leukaemia cells might exploit this newly identified function of AGO2 to sustain their uncontrolled growth,” explains Dr Aleksey Lazarenkov, first author of the study.

Implications for acute myeloid leukaemia

Using international patient databases, the team found increased DNA methylation in a region controlling the AGO2 gene in AML cases with TET2 mutations. This suggests that AGO2 regulation is disrupted in these patients. AGO2 expression and DNA methylation patterns were also associated with patient survival and other clinical features. These findings raise the possibility that these measurements could help assess the likely course of the disease, although further studies are needed to establish their usefulness as biomarkers.

The team then reduced AGO2 levels in leukaemia cells from patients with AML before transplanting the modified cells into mice. Working with Dr Pablo Menendez, Group Leader at the Josep Carreras Institute, they found that these cells were substantially less able to establish and sustain leukaemia. These findings provide functional evidence that AGO2 contributes to leukaemia development and suggest that it could be a potential treatment target. However, whether targeting AGO2 would be safe or effective in patients remains unknown.

“These findings open new avenues for investigating how AGO2 supports leukaemia development and whether this dependency could be exploited therapeutically. More work is needed to understand the underlying mechanisms and establish the potential relevance of this discovery for patients,” says Dr José Luis Sardina, senior author of the study.

This work was funded by Worldwide Cancer Research, the Government of Spain, the Government of Catalonia and the Carlos III Health Institute.

Reference Article: Aleksey Lazarenkov et al. TET2-driven activation of AGO2 links epigenetic remodeling to myeloid commitment and leukemia.Sci. Adv.12,eaee5701(2026).DOI:10.1126/sciadv.aee5701

About the Josep Carreras Leukaemia Research Institute

The Josep Carreras Leukaemia Research Institute is Spain's dedicated research institute for blood cancers, one of the very few free-standing institutes in the world focused exclusively on this disease space.

Founded in 2010, the Institute was recognized in 2024 as a Severo Ochoa Centre of Excellence by the Spanish Ministry of Science, Innovation and Universities. IJC is also a center of excellence CERCA of the Catalan Government and is embedded in a network of six affiliated hospitals across Catalonia. The Institute’s researchers bring together expertise in epigenetics, immunology, stem cell biology, spatial transcriptomics, computational oncology, and clinical investigation, all directed at a single purpose: curing blood cancers.

The Institute's translational strategy is built around three interconnected pillars: the Catalonia Translational Working Groups, which unite clinicians, scientists, and diagnostics experts around the most urgent cross-disease challenges in hematological malignancy; PATH2CURE, a comprehensive therapeutics platform that advances discoveries from target identification through preclinical validation toward clinical application; and the Center for 22nd Century Diagnostics (C22D), a joint initiative with the Barcelona Supercomputing Center that integrates spatial biology, multi-omics, and artificial intelligence to generate dynamic, patient-specific diagnostic models capable of predicting how disease will evolve and resist. Together, these pillars form a continuous translational cycle connecting patient care, biological discovery, and clinical innovation. This is made possible thanks to the philanthropic mission of the Josep Carreras Leukaemia Foundation and by the commitment of every person at the Institute to the patients who cannot afford to wait.