Aberrant overexpression of CD14 on granulocytes sensitizes the innate immune response in mDia1 heterozygous del(5q) MDS

Abstract

Key Points• mDia1 deficiency led to a cellautonomous overexpression of CD14 on granulocytes and a hypersensitive innate immune response.• mDia1 heterozygous and knockout mice developed age-dependent MDS that was accelerated by chronic stimulation of the innate immunity.The myelodysplastic syndromes (MDSs) include a spectrum of stem cell malignancies characterized by an increased risk of developing acute myeloid leukemia. Heterozygous loss of chromosome 5q (del[5q]) is the most common cytogenetic abnormality in MDS. DIAPH1 is localized to 5q31 and encodes one of the formin proteins, mDia1, which is involved in linear actin polymerization. Mice with mDia1 deficiency develop hematologic features with age mimicking human myeloid neoplasm, but its role in the pathogenesis of MDS is unclear. Here we report that mDia1 heterozygous and knockout mice develop MDS phenotypes with age. In these mice, CD14 was aberrantly overexpressed on granulocytes in a cell-autonomous manner, leading to a hypersensitive innate immune response to lipopolysaccharide (LPS) stimuli through CD14/Toll-like receptor 4 signaling. Chronic stimulation with LPS accelerated the development of MDS in mDia1 heterozygous and knockout mice that can be rescued by lenalidomide. Similar findings of CD14 overexpression were observed on the bone marrow granulocytes of del(5q) MDS patients. Mechanistically, mDia1 deficiency led to a downregulation of membrane-associated genes and a specific upregulation of CD14 messenger RNA in granulocytes, but not in other lineages. These results underscore the significance of mDia1 heterozygosity in deregulated innate immune responses in del(5q) MDS. (Blood. 2014;124(5):780-790)

A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss

“…25,39 However, a critical negative regulatory role for DIAPH1 is indicated by the observations that targeted knockout of the murine DIAPH1 ortholog Drf1 resulted in hyperproliferative myelodysplasia. 40,41 Consistent with this, DIAPH1 knockdown in cultured human MKs resulted in increased proplatelet formation. 17 In contrast, overexpression of a constitutively active DIAPH1, in which both the DID and DAD were deleted by artificial mutagenesis (mDiaDN3), reduced proplatelet formation in cultured human MKs.…”

An inflammatory bowel disease–risk variant in INAVA decreases pattern recognition receptor–induced outcomes

“…One reason for this might be a different INAVA expression threshold required for distinct immunological outcomes. Expression/function threshold differences have been observed for various molecules (54,55).…”

Toll-like receptor signaling in hematopoietic homeostasis and the pathogenesis of hematologic diseases

“…Chen et al found that Lin -HLA-DR -CD33 + MDSCs were markedly expanded in the BM of MDS patients [114]. S100A8/ S100A9, which are known endogenous DAMPs [115,116], bind to CD33 to induce the expansion and activity of MDSCs [109,110]. Clonally distinct MDSCs in BM overproduce suppressive cytokines, such as IL-10 and TGF-β as well as nitric oxide (NO) and arginase, thereby contributing to the pathogenesis of MDS by inducing ineffective hematopoiesis.…”

“…The overexpression of CD14 also exacerbates the MDS disease phenotype in mice. These findings may explain why lenalidomide, an immunomodulatory agent, elicits a therapeutic response in patients with del(5q) MDS [110,111].…”

“…DIAPH1, which encodes a RhoA GTPase effector mDia1, regulates the dynamics of the actin cytoskeleton. DIAPH1 is also deleted in del(5q) MDS and upregulates CD14 in neutrophils through an unknown mechanism [110]. As a result, IRAK, TRAF6, and NF-κB are constitutively activated in BM samples of most del(5q) MDS patients.…”