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ChIP-seq of CSF-1R in THP-1 cell lines deleted for EGR1 gene by CRISPR-Cas9 and ChIP-seq of CSF-1R in 2 CMML patients

ABSTRACT: CSF-1R is recruited on EGR1 motifs in monocytes where it colocalizes with EGR1. To address if EGR1 required for CSF-1R recruitment on chromatin, THP-1 monocytic cell line has been deleted for EGR1 by CRISPR-Cas9 approach. 3 clones were generated by single cell cloning and CSF-1R localization on chromatin was compared to two unmodified THP-1 clones by ChIP-sequencing. Since the read number was strongly decreased in the EGR1-deleted clones, the three clones were pooled for the comparison with wild-type clones. ChIPseq of CSF-1R (Nter Antibody) in monocytes of two CMML patients (CMML2130 and CMML2609)

INSTRUMENT(S): Illumina NovaSeq 6000

ORGANISM(S): Homo sapiens

SUBMITTER: Laura Bencheikh

PROVIDER: E-MTAB-7756 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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ChIP-seq of CSF-1R, H3K4me1, H3K4me3 in human primary unstimulated monocytes and monocytes differentiated 72h with CSF-1 (3 healthy donors buffy coat) and in monocytes from two CMML patients and one healthy donor, EGR1 ChIP-seq in unstimulated monocytes (3 healthy donors buffy coat)

Project description:Identification of nuclear CSF-1R, H3K4me1 and H3K4me3 localization on chromatin in human primary monocytes and modification of this localization during monocyte differentiation into macrophage induced by 100ng/mL CSF-1 during 6 hours (1 donor) or 72h (3 donors). Identification of EGR1 chromatin localization in human primary monocytes (3 donors) Comparison of nuclear CSF-1R chromatin localization in monocytes from 1 healthy donor and 2 chronic myelomonocytic leukemia patients.

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CSF-1R inhibition alters macrophage polarization and blocks gliomagenesis

Project description:Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor in adults, can be divided into several molecular subtypes including proneural GBM. Most clinical strategies aimed at directly targeting glioma cells in these tumors have failed. A promising alternative is to target stromal cells in the brain microenvironment, such as tumor-associated microglia and macrophages (TAMs). Macrophages are dependent upon colony stimulating factor (CSF)-1 for differentiation and survival; therefore, we used an inhibitor of its receptor, CSF-1R, to target macrophages in a mouse proneural GBM model. CSF-1R inhibition dramatically increased survival in mice and regressed established GBMs. Tumor cell apoptosis was significantly increased, and proliferation and tumor grade markedly decreased. Surprisingly, TAMs were not depleted in tumors treated with the CSF-1R inhibitor. Instead, analysis of gene expression in TAMs isolated from treated tumors revealed a decrease in alternatively activated/ M2 macrophage markers, consistent with impaired tumor-promoting functions. These gene signatures were also associated with better survival specifically in the proneural subtype of patient gliomas. Collectively, these results establish macrophages as valid therapeutic targets in proneural gliomas, and highlight the clinical potential for CSF-1R inhibitors in GBM. RNA was isolated from sorted tumor associated macrophages (TAMs) from murine gliomas following either 7 days of vehicle or BLZ945 treatment. Samples were collected from 16 total tumor burdened mice, with 8 replicates for each treatment group. BLZ945: a Colony-Stimulating Factor 1 Receptor (CSF-1R) inhibitor

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CSF-1R inhibition alters macrophage polarization and blocks gliomagenesis

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ChIP-seq of CSF-1R in THP-1 cell lines deleted for EGR1 gene by CRISPR-Cas9 and ChIP-seq of CSF-1R in 2 CMML patients

Project description:ChIP-seq of CSF-1R in THP-1 cell lines deleted for EGR1 gene by CRISPR-Cas9 and ChIP-seq of CSF-1R in 2 CMML patients

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A paracrine IGF1/IGF1R-PI3K signaling loop underlies resistance to CSF-1R inhibition in GBM

Project description:Glioblastoma multiforme (GBM) is the most aggressive form of glioma, and is notorious for its terminal prognosis and lack of responsiveness to current treatment approaches. The brain tumor microenvironment (TME) represents a largely untapped reservoir of therapeutic target options in GBM. Here we have focused on the interplay between glioma cells and tumor-associated macrophages/ microglia (TAMs). TAMs accumulate in the gliomas with disease progression, and depend on colony stimulating factor 1 receptor (CSF-1R) signaling for survival. In a recent study from our laboratory, mice bearing high-grade gliomas were treated with a CSF-1R inhibitor, BLZ945 (Novartis), and tumors regressed significantly after just 7 days of treatment (PMID: 24056773). Here we investigate whether long-term treatment of high-grade gliomas with BLZ945 would result in stable management of disease in a mouse model of proneural GBM. We show that ~44% of mice survived to the trial end point (EP) with minimal disease by MRI and histology, whereas ~56% of mice showed tumor recurrence (Reb). Serial transplantation of rebound tumor cells into naïve animals re-established BLZ945 responsiveness, suggesting a role for the microenvironment in supporting recurrent disease. Indeed, RNA-seq analysis on FACS purified tumor cells and TAMs from EP and Reb tumors showed elevated PI3K signaling in Reb tumors, driven by a heterotypic paracrine interaction between TAM-derived IGF-1 and tumor cell IGF-1R. We performed combination trials to block IGF-1R or downstream PI3K signaling in rebound tumors with BLZ945 treatment, and were able to significantly prolong overall survival. Given that CSF-1R inhibitors are currently in clinical trials for multiple cancer types including for GBM, understanding the molecular mechanisms that underlie non-responsive/ resistant tumors is timely and critical.

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Microenvironment-driven IGF-1R/PI3K signaling underlies acquired resistance to CSF1R inhibition in gliomas (CGH)

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