Persistent Immune Stimulation Exacerbates Genetically Driven Myeloproliferative Disorders via Stromal Remodeling

Area of Science:

• Immunology
• Oncology
• Hematology

Background:

• Systemic immune stimulation is linked to myeloid malignancies, but the underlying mechanisms remain unclear.
• The bone marrow microenvironment plays a critical role in hematopoietic stem cell regulation and malignancy development.

Purpose of the Study:

• To investigate the pathogenic link between systemic immune activation and myeloid malignancies.
• To elucidate the role of the bone marrow microenvironment and neutrophil extracellular traps (NETs) in the development and progression of NPM1-mutated acute myeloid leukemia (AML).

Main Methods:

• Animal models of systemic immune activation were used to study bone marrow stromal microenvironment changes.
• Analysis of extracellular matrix (ECM) components, immune cell populations, and hematopoietic precursor behavior.
• Identification and validation of a NET-related inflammatory gene signature in human myeloid malignancies, including AML patients.

Main Results:

• Systemic immune activation altered the bone marrow microenvironment, decreasing SPARC and collagen-I, and increasing complement activation.
• These changes promoted immunogenic death of NPM1-mutated hematopoietic precursors, leading to NET formation.
• NETs exacerbated indolent myeloproliferation into a dysplastic phenotype, and NET enrichment was observed in AML patients.

Conclusions:

• Stromal/ECM changes and NETosis priming by systemic inflammation contribute to myeloid malignancy development and progression.
• A NET-related gene signature can identify AML subsets and predict response to immunomodulatory drugs.
• Targeting NET formation may offer therapeutic strategies for myeloid malignancies associated with inflammation.