Early detection of cancer recurrence using specific biomarkers remains a clinically unmet need, although methodologies for monitoring tumor markers, cell-free DNA, and circulating tumor cells have been established for decades. Tumor recurrence develops in metastatic or dormant cancer cells under continuous immune surveillance. Alterations in the population and function of immune cells may contribute to cancer recurrence. Here, we utilized an animal model to imitate breast tumor recurrence after surgical resection and investigated the abundance and gene expression profiles of immune cells using NanoString analysis. Bioinformatic analysis of a published single-cell RNA sequencing database of myeloid-derived suppressor cells (MDSCs) was performed to identify common targets between the two studies. Identified biomarkers were validated using human peripheral blood mononuclear cell (PBMC) datasets. The inhibitory effect of MDSCs on T-cell proliferation was assessed in vitro. Our data demonstrated that the number of MDSCs significantly increased during recurrence. Comparison of our NanoString data with a single-cell RNA sequencing dataset of MDSCs in another spontaneous breast cancer model identified colony-stimulating factor 3 receptor (Csf3r)-positive MDSCs as a potential marker for predicting tumor relapse. We validated our findings using two previously published PBMC databases of patients with breast cancer with or without recurrence and confirmed the elevated MDSC gene signature and CSF3R expression in patients with tumor recurrence. 35 patients with breast cancer were also included in our study, that patients with higher levels of CSF3R had worse survival. In vitro experiments demonstrated that Csf3r + MDSCs exhibited enhanced reactive oxygen species (ROS) levels and robust T-cell suppression ability. We conclude that an increase in CSF3R + MDSCs is a potential biomarker for early detection of tumor recurrence in patients with breast cancer.

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Gliomas comprise most cases of central nervous system (CNS) tumors. Gliomas afflict both adults and children, and glioblastoma (GBM) in adults represents the clinically most important type of malignant brain cancer, with a very poor prognosis. The cell surface glycoprotein CD114, which is encoded by the CSF3R gene, acts as the receptor for the granulocyte colony stimulating factor (GCSF), and is thus also called GCSFR or CSFR. CD114 is a marker of cancer stem cells (CSCs), and its expression has been reported in several cancer types. In addition, CD114 may represent one among various cases where brain tumors hijack molecular mechanisms involved in neuronal survival and synaptic plasticity. Here, we describe CSF3R mRNA expression in human gliomas and their association with patient prognosis as assessed by overall survival (OS). We found that the levels of CSF3R/CD114 transcripts are higher in a few different types of gliomas, namely astrocytoma, pilocytic astrocytoma, and GBM, in comparison to non-tumoral neural tissue. We also observed that higher expression of CSF3R/CD114 in gliomas is associated with poorer outcome as measured by a shorter OS. Our findings provide early evidence suggesting that CSF3R/CD114 shows a potential role as a prognosis marker of OS in patients with GBM.

Myeloproliferative neoplasms (MPNs) are hematopoietic diseases characterized by the clonal expansion of single or multiple lineages of differentiated myeloid cells that accumulate in the blood and bone marrow. MPNs are grouped into distinct categories based on key clinical presentations and distinctive mutational hallmarks. These include chronic myeloid leukemia (CML), which is strongly associated with the signature BCR::ABL1 gene translocation, polycythemia vera (PV), essential thrombocythemia (ET), and primary (idiopathic) myelofibrosis (PMF), typically accompanied by molecular alterations in the JAK2, MPL, or CALR genes. There are also rarer forms such as chronic neutrophilic leukemia (CNL), which involves mutations in the CSF3R gene. However, rather than focusing on the differences between these alternate disease categories, this review aims to present a unifying molecular etiology in which these overlapping diseases are best understood as disruptions of normal hematopoietic signaling: specifically, the chronic activation of signaling pathways, particularly involving signal transducer and activator of transcription (STAT) transcription factors, most notably STAT5B, leading to the sustained stimulation of myelopoiesis, which underpins the various disease sequalae.

Chronic myelomonocytic leukemia (CMML) is a hematological neoplasm characterized by monocytosis, splenomegaly, thrombocytopenia, and anemia. Moreover, it is associated with SRSF2 mutations and, rarely, with CSF3R variants. We present the case of an 84-year-old patient with persistent anemia and monocytosis. Due to the presence of dysmorphic granulocytes, monocyte atypia, and myeloid precursors in the peripheral blood cells, the patient was subjected to a bone marrow examination. The diagnosis was consistent with CMML type 2. The Hemocoagulative test showed an increase in fibrinolysis markers. Next-generation targeted sequencing showed TET2 and SRSF2 mutations, along with an unexpected CSF3R germline missense variant, rarely encountered in CMML. The patient started Azacitidine treatment and achieved normal hemostatic process values. In conclusion, we identified a heterozygous germline mutation that, together with TET2 and SRSF2 variants, was responsible for the hemorrhagic manifestation.

BACKGROUND: Osteosarcoma (OS) is a common primary malignant bone tumor that mainly occurs in children and adolescents. The use of IL-8 inhibitor compounds has been reported in patents, which can be used to treat and/or prevent osteosarcoma, but the pathogenesis of osteosarcoma remains to be investigated. At present, osteoblasts and osteoclasts play an important role in the occurrence and development of OS. However, the relationship between osteoblasts and osteoclasts in the specific participation mechanism and inflammatory response of OS patients has not been further studied.
METHODS: The transcriptome, clinical data, and other data related to OS were downloaded from the GEO database to analyze them with 200 known inflammatory response genes. We set the screening conditions as p < 0.05 and | log2FC| > 0.50, screened the differentially expressed genes (DEGs) related to OS, tested the correlation coefficient between the OS INF gene and clinical risk, and analyzed the survival prognosis. We further enriched and analyzed the DEGs and inflammatory response genes of OS with GO/KEGG to explore the potential biological function and signal pathway mechanism of OS inflammatory response genes. Moreover, the virtual screening of drug sensitivity of OS based on the FDA drug library was also carried out to explore potential therapeutic drugs targeted to regulate OS osteogenesis and osteoclast inflammation, and finally, the molecular dynamics simulation verification of OS core protein and potential drugs was carried out to explore the binding stability and mechanism between potential drugs and core protein.
RESULTS: Through differential analysis of GSE39058, GSE36001, GSE87624, and three other data sets closely related to OS osteoblasts and osteoclasts, we found that there was one upregulated gene (CADM1) and one down-regulated gene (PHF15) related to OS. In addition, GSEA enrichment analysis of the DEGs of OS showed that it was mainly involved in the progress of OS through biological functions, such as oxidative photosynthesis, acute junction, and epithelial-mesenchymal transition. The enrichment analysis of OS DEGs revealed that they mainly affect the occurrence and progress of OS by participating in the regulation of the actin skeleton, PI3K Akt signal pathway, complement and coagulation cascade. According to the expression of CSF3R in OS patients, a risk coefficient model and a diagnostic model were established. It was found that the more significant the difference in the CSF3R gene in OS patients, the greater the risk coefficient of disease (p < 0.05). The AUC under the curve of the CSF3R gene was greater than 0.65, which had a good diagnostic significance for OS. The above results showed that the prognosis risk gene CSF3R related to OS inflammation was closely related to the survival status of OS patients. Finally, through the virtual screening of the ZINC drug library and molecular dynamics simulation, it was found that the docking model formed by the core protein CSF3R and the compounds, Leucovorin and Methotrexate, were the most stable, which revealed that the compounds Leucovorin and Methotrexate might play a role in the treatment of OS by combining with the inflammatory response related factor CSF3R of OS.
CONCLUSIONS: CSF3R participates in the occurrence and development of OS bone destruction by regulating the inflammatory response of osteoblasts and osteoclasts and can affect the survival prognosis of OS patients.

Chronic neutrophilic leukemia (CNL) is primarily diagnosed by excluding myelodysplastic syndromes (MDS). We report the case of a patient who developed secondary CNL 3 years after hypoplastic MDS. We used droplet digital polymerase chain reaction mutation detection assay to analyze genomic alterations during the progression from MDS to CNL. At the time of MDS diagnosis, U2AF1 Q157P and SETBP1 D868N were dominant and additional mutation of ASXL1 1934_insG was observed. CSF3R T618I and SETBP1 D868N were increasing at the time of CNL diagnosis. We revealed the accumulation of multiple gene mutations during CNL development from MDS. This suggests that CNL was clonally developed from the founding clone of MDS and CSF3R mutation contributes to the development of CNL in the present case. These findings provide insights into the pathology of CNL.

The pathogenesis of hematological tumors has not been fully elucidated. The academic community believes that genetic mutation abnormalities play a crucial role in the occurrence and development of hematological malignancies. Chronic neutrophilic leukemia (CNL) is a rare hematological tumor in the world. It is characterized by a Philadelphia chromosome BCR-ABL1-negative myeloproliferative tumor. It can be accompanied by mutations in various genes. Colony-stimulating factor 3 receptor (CSF3R) is a classic mutation in CNL and is included in the diagnostic criteria for CNL. This article described a 46-year-old male patient who came to the hospital with non-specific clinical manifestations such as unrelieved abdominal distension and edema of both lower extremities as the primary symptoms. The middle-aged male patient was provided with a peripheral a routine blood test. The biochemical tests revealed abnormalities. A bone marrow biopsy was performed to complete various tests such as bone marrow morphology, immunology, molecular biology, cytogenetics, and imaging. He was diagnosed with a rare chronic neutrophilic leukemia. After the diagnosis, the patient took ruxolitinib orally targeted therapy as prescribed by the doctor. Doctors regularly reviewed the peripheral blood examination and bone marrow status. The current condition is well controlled. CNL is extremely rare. The disease usually has non-specific clinical features and manifestations as the primary symptoms. These symptoms can easily be missed or lead to misdiagnosed ailments by clinicians. It is necessary to increase the awareness and vigilance of CNL.

Colony-stimulating factor 3 receptor (CSF3R) has been demonstrated to be associated with various hematological tumors, especially chronic neutrophilic leukemia; however, the detailed roles of CSF3R in other cancers remain to be explored.
In the present study, we systematically analyzed the expression profiles of CSF3R in pan-cancer by comprehensive bioinformatics databases, such as Tumor Immune Estimation Resource, version 2 (TIMER2.0), Gene Expression Profiling Interactive Analysis, version 2 (GEPIA2.0), etc. GEPIA2.0 was also used to analyze the relationship between CSF3R expression and patients\' survival prognosis.
We found that the high expression of CSF3R was associated with a poor prognosis in the brain tumor patients, such as brain lower grade glioma and glioblastoma multiforme. In addition, we further investigated the genetic mutation and DNA methylation level of CSF3R in multiple cancers. Immune infiltration analysis showed that CSF3R expression was positively correlated with a variety of tumor-infiltrating immune cells in most cancers. Single cell sequencing indicated that CSF3R levels were correlated with several cancer-associated pathways, such as DNA damage, cell invasion, and stemness.
Taken together, the role of CSF3R in multiple cancers might reveal its potential as a novel prognostic biomarker and therapeutic target for cancer patients.

We describe a patient with congenital neutropenia (CN) with a homozygous germline mutation in the colony-stimulating factor 3 receptor gene (CSF3R). The patient\'s bone marrow shows lagging neutrophil development with subtle left shift and unresponsiveness to CSF3 in in vitro colony assays. This patient illustrates that the di-proline hinge motif in the extracellular cytokine receptor homology domain of CSF3R is critical for adequate neutrophil production, but dispensable for in vivo terminal neutrophil maturation. This report underscores that CN patients with inherited CSF3R mutations should be marked as a separate clinical entity, characterized by a failure to respond to CSF3.