ActivinA Helps B-ALL Cells by Inducing Extracellular Vesicles

ActivinA appears to support the survival of leukemia cells by promoting extracellular vesicle (EV)-mediated crosstalk in patients with B-cell acute lymphoblastic leukemia (B-ALL), according to a new report.

The study, which was published in Scientific Reports, builds on existing research into the role of ActivinA in other cancers, offering new insights into how the cytokine interacts with leukemia.¹ The authors say the findings could help drug developers better identify strategies for counteracting it.

Although the long-term survival rate for patients with B-ALL is relatively high, about 1 in 5 individuals who achieve complete remission will experience relapse, wrote the study authors. One factor believed to contribute to relapse is the altered leukemic bone marrow (BM) microenvironment, which they said becomes “a sanctuary in which stromal cells communicate with leukemic B cells by taking direct contact; secreting soluble factors, including metabolites; and releasing extracellular vesicles.”

Identifying and targeting altered molecules involved in the leukemia-stroma crosstalk might help improve outcomes in patients with B-ALL, they explained.

As a first step, the authors said they decided to focus on ActivinA. They noted that ActivinA has been implicated in promoting multiple solid malignancies and has been shown to be upregulated in the BM of patients with B-ALL. They previously demonstrated that ActivinA is “strongly” induced by mesenchymal stromal cells that were cultured with leukemic cells.² They also found that ActivinA enhances the migratory and invasive properties of leukemia cells, and noted that the release of EVs—which are seen as an important mechanism of intracellular communication—is “dependent upon cytoskeleton activation and membrane remodeling.”

In solid tumors like breast and pancreatic cancer, the authors said increasing evidence suggests EVs play an important pathogenic role in tumor survival and treatment resistance. Yet, they said there is limited existing evidence related to the role of EVs in B-ALL.

In their new study, they investigated how ActivinA affects B-ALL cell vesiculation and leukemic cell survival under stress conditions, including nutrient starvation.

The investigators found that leukemic cells’ release of EVs increases in response to ActivinA. In culture-induced stress conditions, coculturing EVs with B-ALL cells promoted survival of the B-ALL cells in a dose-dependent manner.

“Direct stimulation of B-ALL cells with ActivinA or with EVs isolated from ActivinA-stimulated cells was even more effective in preventing cell death,” they added.

One possible reason, they said, is that ActivinA increases vesiculation and modifications of EV-associated microRNAs.

They said the findings suggest possible pathways forward for future investigation, such as finding a means to sequester ActivinA might help counteract the proleukemic effects observed in the study.

“Indeed, ActivinA blocking by specific molecular traps would be a valuable option to modulate the crosstalk between leukemic cells and potentially make B-ALL cells more sensitive to apoptosis induced by metabolic stress-inducing chemotherapeutics,” they wrote.

They said research into possible molecular traps for ActivinA is already underway in other diseases, including within the context of myelodysplastic syndromes and pulmonary arterial hypertension. A report published in November 2023 suggested a potential trap for activins including ActivinA was well tolerated and offered an “encouraging” duration of response.³

More research is needed, they concluded, to see how such traps might work in the context of leukemia, both as a standalone therapy and in combination with chemotherapy.

References

1. Licari E, Cricrì G, Mauri M, et al. ActivinA modulates B-acute lymphoblastic leukaemia cell communication and survival by inducing extracellular vesicles production. Sci Rep. Published online July 12, 2024. doi:10.1038/s41598-024-66779-3

2. Portale F, Cricrì G, Bresolin S, et al. ActivinA: a new leukemia-promoting factor conferring migratory advantage to B-cell precursor-acute lymphoblastic leukemic cells. Haematologica. 2019;104(3):533-545. doi:10.3324/haematol.2018.188664

3. Diez-Campelo M, Ross DM, Giagounidis A, et al. Durable clinical benefit with Ker-050 treatment: findings from an ongoing phase 2 study in participants with lower-risk MDS. Blood. 2023;142(suppl 1):196. doi:10.1182/blood-2023-180974