A proinflammatory stem cell niche drives myelofibrosis through a targetable galectin-1 axis

Area of Science:

• Hematology
• Oncology
• Immunology

Background:

• Myeloproliferative neoplasms (MPNs) are stem cell cancers with significant morbidity and mortality.
• Progression to myelofibrosis or leukemia is common, with poor prognosis and limited treatment options.
• Understanding cellular interactions in MPNs is crucial for developing new therapies.

Purpose of the Study:

• To comprehensively map cell-cell communication in myelofibrotic bone marrow.
• To identify key drivers of inflammation and fibrosis in MPNs.
• To discover novel biomarkers and therapeutic targets for myelofibrosis.

Main Methods:

• Comprehensive analysis of cell cross-talk in myelofibrotic bone marrow.
• Identification of a specific cellular quartet orchestrating inflammation and fibrosis.
• In vitro and in vivo studies of galectin-1 inhibition.
• Analysis of human bone marrow organoids.

Main Results:

• A quartet of immune and stromal cells (basophils, mast cells, megakaryocytes, mesenchymal stromal cells) drives TNF signaling, inflammation, and fibrosis.
• Galectin-1 identified as a biomarker for myelofibrosis progression and poor survival.
• Galectin-1 inhibition reduced myeloproliferation and fibrosis in vitro and in vivo, improving survival.
• TNF signaling creates a feedback loop that promotes MPN progression.

Conclusions:

• Cellular interactions, particularly involving a TNF signaling hub, are critical in MPN progression to myelofibrosis.
• Galectin-1 is a promising therapeutic target and biomarker for myelofibrosis.
• Targeting galectin-1 offers a potential strategy to prevent or reverse fibrosis and improve patient outcomes.