Cooperating, congenital neutropenia–associated Csf3r and Runx1 mutations activate pro-inflammatory signaling and inhibit myeloid differentiation of mouse HSPCs

Abstract

Patients with the pre-leukemia bone marrow failure syndrome called severe congenital neutropenia (CN) have an approximately 15% risk of developing acute myeloid leukemia (AML; called here CN/AML). Most CN/AML patients co-acquire CSF3R and RUNX1 mutations, which play cooperative roles in the development of AML. To establish an in vitro model of leukemogenesis, we utilized bone marrow lin− cells from transgenic C57BL/6-d715 Csf3r mice expressing a CN patient–mimicking truncated CSF3R mutation. We transduced these cells with vectors encoding RUNX1 wild type (WT) or RUNX1 mutant proteins carrying the R139G or R174L mutations. Cells transduced with these RUNX1 mutants showed diminished in vitro myeloid differentiation and elevated replating capacity, compared with those expressing WT RUNX1. mRNA expression analysis showed that cells transduced with the RUNX1 mutants exhibited hyperactivation of inflammatory signaling and innate immunity pathways, including IL-6, TLR, NF-kappaB, IFN, and TREM1 signaling. These data suggest that the expression of mutated RUNX1 in a CSF3R-mutated background may activate the pro-inflammatory cell state and inhibit myeloid differentiation.

Integrated transcriptome, proteome and single‐cell sequencing uncover the prognostic and immunological features of colony‐stimulating factor 3 receptor in pan‐cancer

“…28,29 Cells with RUNX1 and CSF3R mutants exhibited the hyperactivation of inflammatory and immune signaling pathways, involving in the development of LAML. 30 CXCL9 may play a protective role in pulmonary fibrosis through abrogating the EMT induced by anti-inflammation factor TGF-β1. 31 Moreover, tumor-infiltrating lymphocyte-based therapeutic strategies also improve the clinical management of cancer patients, providing a remarkable perspective in tumor therapy.…”

“…In recent years, increasing studies have shown that tumor immune microenvironment is related to a variety of clinical biological functions in cancers, affecting cancer pathogenesis and the therapeutic response 28,29 . Cells with RUNX1 and CSF3R mutants exhibited the hyperactivation of inflammatory and immune signaling pathways, involving in the development of LAML 30 . CXCL9 may play a protective role in pulmonary fibrosis through abrogating the EMT induced by anti‐inflammation factor TGF‐β1 31 .…”