Persistent Immune Stimulation Exacerbates Genetically Driven Myeloproliferative Disorders via Stromal Remodeling

Abstract

Systemic immune stimulation has been associated with increased risk of myeloid malignancies, but the pathogenic link is unknown. We demonstrate in animal models that experimental systemic immune activation alters the bone marrow stromal microenvironment, disarranging extracellular matrix (ECM) microarchitecture, with downregulation of secreted protein acidic and rich in cysteine (SPARC) and collagen-I and induction of complement activation. These changes were accompanied by a decrease in Treg frequency and by an increase in activated effector T cells. Under these conditions, hematopoietic precursors harboring nucleophosmin-1 (NPM1) mutation generated myeloid cells unfit for normal hematopoiesis but prone to immunogenic death, leading to neutrophil extracellular trap (NET) formation. NET fostered the progression of the indolent NPM1-driven myeloproliferation toward an exacerbated and proliferative dysplastic phenotype. Enrichment in NET structures was found in the bone marrow of patients with autoimmune disorders and in NPM1-mutated acute myelogenous leukemia (AML) patients. Genes involved in NET formation in the animal model were used to design a NET-related inflammatory gene signature for human myeloid malignancies. This signature identified two AML subsets with different genetic complexity and different enrichment in NPM1 mutation and predicted the response to immunomodulatory drugs. Our results indicate that stromal/ECM changes and priming of bone marrow NETosis by systemic inflammatory conditions can complement genetic and epigenetic events towards the development and progression of myeloid malignancy.

The Immune Checkpoint Modulator OX40 and Its Ligand OX40L in NK-Cell Immunosurveillance and Acute Myeloid Leukemia

“…It seems thus possible that OX40 confers a survival benefit for leukemic cells that is enacted through interaction with OX40L-bearing immune or bystander cells. This is in line with evidence regarding the role of the immune and stromal microenvironment in malignancies in general, which also holds true for AML (38). Moreover, these findings concur with our hypothesis regarding therapeutic application of "untargeted" agonistic OX40 mAb.…”

Transcriptional Profiles and Stromal Changes Reveal Bone Marrow Adaptation to Early Breast Cancer in Association with Deregulated Circulating microRNAs

“…Bone marrow stromal niches are essential for the maintenance and regulation of hematopoietic stem cells and of their lineage differentiation (42,43). Also, stromal remodeling occurs in response to stress conditions or in case of hematologic disorders (8,14,44). Much less is known on bone marrow stromal niche alterations associated to distant solid tumor, independently from bone marrow metastatic colonization.…”

“…Four-micrometer-thick sections were used for both histopathology and immunostaining. IHC was performed using the horseradish peroxidase method as reported previously (14). See Supplementary Materials and Methods for a list of antibodies.…”

Understanding deregulated cellular and molecular dynamics in the haematopoietic stem cell niche to develop novel therapeutics for bone marrow fibrosis

“…These data led to the hypothesis that Gli1 + stromal cells are activated from their niche by atypical platelets/megakaryocytes (mediated by Cxcl4), which leads to a cascade of myofibroblast transdifferentiation, metabolic reprogramming, and downregulation of Cxcl12. Additional stimuli might be derived from mutant neutrophils that additionally lead to persistent immune stimulation [57].…”