Neutrophil Subset Changes Give Insight Into First Mechanisms of MDS, AML

Low-density granulocyte (LDG) and normal-density neutrophil (NDN) subset changes identified in a recent study suggest that emergency hemopoiesis may be a first mechanism to maintain peripheral blood counts, but also a proinflammatory microenvironment, in patients with myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and idiopathic cytopenia of unknown significance (ICUS).1

In patients with MDS and AML, the researchers found impaired neutrophil subset distribution compared with healthy individuals. | Image credit: keetazalay - stock.adobe.com

The clinical course of MDS is known to vary among patients, with excessive molecular and functional heterogeneity thought to drive the different patient experiences.2 The new findings, published in Scientific Reports,1 are the first to describe distributions and perturbations of LDG and NDN subsets in AML, MDS, and ICUS. The authors explored variations in LDG and NDN distribution hematological conditions via optimized 10-color flow cytometry staining to immunophenotype the main circulating populations.

“Neutrophils can promote or suppress tumor growth. These different immunological functions mirror a great heterogenicity of neutrophil maturation and activation status: low-density granulocytes and normal-density neutrophils,” the authors explained. “LDGs participate in immune dysregulation during autoimmune disorders with an activated phenotype, while NDNs might exert immunosuppressive activities.”

The observational study included 102 subjects screened for malignant hematological conditions between January 2020 and December 2024 in the Hematology and Transplant Center at the University Hospital San Giovanni di Dio e Ruggi d’Aragona in Salerno, Italy. Twelve patients were diagnosed with AML, 39 with MDS, and 10 with ICUS, and the remaining patients had other hematological malignancies. A cohort of healthy subjects without cytopenias or other inflammatory or pathological conditions was used as a control group.

In patients with MDS and AML, the researchers found impaired neutrophil subset distribution compared with healthy individuals. Intermediate and mature LDGs were also significantly reduced in these patients. These factors showed good diagnostic sensitivity in both MDS and AML. In MDS, impaired neutrophil subset distribution showed an area under the curve (AUC) of 0.793 (P = .0013), while reduced intermediate and mature LDGs showed an AUC of 0.7319 (P = .0109). In AML, impaired neutrophil subset distribution showed an AUC of 0.9059 (P = .0069), and reduced intermediate and mature LDGs showed an AUC of 0.9176 (P = .00057).

“In our study, LDGs were positively associated with normal hemoglobin levels; conversely, more immature LDG forms with lower levels, while negatively related to percent of circulating blasts, as well as circulating monocytes,” the authors wrote. “Indeed, granulocyte subset distribution seemed to vary based on disease severity, as mature LDGs were highest in healthy and ICUS subjects, while gradually decreased from low- to high-risk MDS, and were the lowest in AML patients, while intermediate LDGs were highly represented in AML and MDS patients.”

With evidence that LDG and NDN subsets may be altered in AML and MDS—favoring more immature forms—the study authors suggested that emergency hemopoiesis could be a first mechanism to sustain peripheral blood counts. But emergency hemopoiesis could also be harmful in the long term as leukemic clones increase and immune responses shut down, the authors explained.

The observed perturbations also indicated that there may be a gradual change from normal to dysplastic hemopoiesis, then to leukemic evolution, the authors noted.

The study was limited by a short follow-up period and small sample size, and there were few cases of disease progression or death, meaning they could not explore the prognostic role of variations in granulocyte subset distribution in MDS or AML. In subjects with ICUS, the authors were not able to investigate the granulocyte subset distribution variations’ potential to predict MDS. There was also a lack of sequential immunophenotyping to compare characteristics before and after therapies in the entire cohort. More research is also needed to identify correlations between impaired neutrophil subset distribution and proinflammatory and protumorigenic functions.

“In conclusion, we described for the first time, even in a small cohort of hematological patients, distributions and perturbations of LDG and NDN subsets in AML, MDS, and ICUS, suggesting that emergency hemopoiesis could be a first mechanism to sustain peripheral blood counts; however, the release of immature granulocytes with proinflammatory activities could maintain a pro-leukemogenic environment and immune selection of neoplastic clones, thus favoring clonal evolution,” the authors wrote.

References

1. Bertolini A, Picone F, Ferrara I, et al. Immature forms of low density granulocytes are increased in acute myeloid leukemia and myelodysplastic syndromes. Sci Rep. Published online March 13, 2025. doi:10.1038/s41598-025-92513-8
2. Valent P. ICUS, IDUS, CHIP and CCUS: diagnostic criteria, separation from MDS and clinical implications. Pathobiology. 2019;8(1):30-38. doi:10.1159/000489042