PUBLICATION
Lactate accumulation promotes immunosuppression and fibrotic transformation of bone marrow microenvironment in myelofibrosis
- Authors
- Spampinato, M., Giallongo, C., Giallongo, S., Spina, E., Duminuco, A., Longhitano, L., Caltabiano, R., Salvatorelli, L., Broggi, G., Pricoco, E.P., Del Fabro, V., Dulcamare, I., DI Mauro, A.M., Romano, A., Di Raimondo, F., Li Volti, G., Palumbo, G.A., Tibullo, D.
- ID
- ZDB-PUB-250115-6
- Date
- 2025
- Source
- Journal of translational medicine 23: 6969 (Journal)
- Registered Authors
- Keywords
- Lactate, Monocarboxylate transporters, Myelofibrosis, Tumor microenvironment
- MeSH Terms
-
- Primary Myelofibrosis*/metabolism
- Primary Myelofibrosis*/pathology
- Fibrosis*
- Pyrimidinones
- Animals
- Immunosuppression Therapy
- Thiophenes
- Mesenchymal Stem Cells/metabolism
- Mesenchymal Stem Cells/pathology
- Female
- Aminopyridines/pharmacology
- Monocarboxylic Acid Transporters*/metabolism
- Symporters/metabolism
- Bone Marrow*/metabolism
- Bone Marrow*/pathology
- Tumor Microenvironment
- Humans
- Male
- Lactic Acid*/metabolism
- Middle Aged
- PubMed
- 39810250 Full text @ J Transl Med
Citation
Spampinato, M., Giallongo, C., Giallongo, S., Spina, E., Duminuco, A., Longhitano, L., Caltabiano, R., Salvatorelli, L., Broggi, G., Pricoco, E.P., Del Fabro, V., Dulcamare, I., DI Mauro, A.M., Romano, A., Di Raimondo, F., Li Volti, G., Palumbo, G.A., Tibullo, D. (2025) Lactate accumulation promotes immunosuppression and fibrotic transformation of bone marrow microenvironment in myelofibrosis. Journal of translational medicine. 23:6969.
Abstract
Background Clonal myeloproliferation and fibrotic transformation of the bone marrow (BM) are the pathogenetic events most commonly occurring in myelofibrosis (MF). There is great evidence indicating that tumor microenvironment is characterized by high lactate levels, acting not only as an energetic source, but also as a signaling molecule.
Methods To test the involvement of lactate in MF milieu transformation, we measured its levels in MF patients' sera, eventually finding a massive accumulation of this metabolite, which we showed to promote the expansion of immunosuppressive subsets. Therefore, to assess the significance of its trafficking, we inhibited monocarboxylate transporter 1 (MCT1) by its selective antagonist, AZD3965, eventually finding a mitigation of lactate-mediated immunosuppressive subsets expansion. To further dig into the impact of lactate in tumor microenvironment, we evaluated the effect of this metabolite on mesenchymal stromal cells (MSCs) reprogramming.
Results Our results show an activation of a cancer-associated phenotype (CAF) related to mineralized matrix formation and early fibrosis development. Strikingly, MF serum, enriched in lactate, causes a strong deposition of collagen in healthy stromal cells, which was restrained by AZD3965. To corroborate these outcomes, we therefore generated for the first time a TPOhigh zebrafish model for the establishment of experimental fibrosis. By adopting this model, we were able to unveil a remarkable increase in lactate concentration and monocarboxylate transporter 1 (MCT1) expression in the site of hematopoiesis, associated with a strong downregulation of lactate export channel MCT4. Notably, exploiting MCTs expression in biopsy specimens from patients with myeloproliferative neoplasms, we found a loss of MCT4 expression in PMF, corroborating changes in MCT expression during BM fibrosis establishment.
Conclusions In conclusion, our results unveil lactate as a key regulator of immune escape and BM fibrotic transformation in MF patients, suggesting MCT1 blocking as a novel antifibrotic strategy.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping