Persistent immune stimulation exacerbates genetically driven myeloproliferative disorders via stromal remodeling

Claudio Tripodo, Alessia Burocchi, Pier Paolo Piccaluga, Claudia Chiodoni, Paola Portararo, Barbara Cappetti, Laura Botti, Alessandro Gulino, Alessandro Isidori, Arcangelo Liso, Giuseppe Visani, Maria Paola Martelli, Brunangelo Falini, Pier Paolo Pandolfi, Mario P. Colombo, Sabina Sangaletti

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)3685-3699
Number of pages15
JournalCancer Research
Volume77
Issue number13
DOIs
Publication statusPublished - Jul 1 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Persistent immune stimulation exacerbates genetically driven myeloproliferative disorders via stromal remodeling'. Together they form a unique fingerprint.

Cite this