Colony-stimulating Factor Receptor Gene Research Articles

The Phenotypic and Genotypic Spectrum of CSF1R-Related Disorder in China.

Colony-stimulating factor 1 receptor (CSF1R)-related disorder (CRD) is a rare autosomal dominant disease. The clinical and genetic characteristics of Chinese patients have not been elucidated. The objective of the study is to clarify the core features and influence factors of CRD patients in China. Clinical and genetic-related data of CRD patients in China were collected. Mini-Mental State Examination (MMSE), Montreal Cognitive Assessment (MoCA), and Sundal MRI Severity Score were evaluated. Whole exome sequencing was used to analyze the CSF1R mutation status. Patients were compared between different sexes, mutation types, or mutation locations. A total of 103 patients were included, with a male-to-female ratio of 1:1.51. The average age of onset was (40.75 ± 8.58). Cognitive impairment (85.1%, 86/101) and parkinsonism (76.2%, 77/101) were the main clinical symptoms. The most common imaging feature was bilateral asymmetric white matter changes (100.0%). A total of 66 CSF1R gene mutants (22 novel mutations) were found, and 15 of 92 probands carried c.2381 T > C/p.I794T (16.30%). The MMSE and MoCA scores (17.0 [9.0], 11.90 ± 7.16) of female patients were significantly lower than those of male patients (23.0 [10.0], 16.36 ± 7.89), and the white matter severity score (20.19 ± 8.47) of female patients was significantly higher than that of male patients (16.00 ± 7.62). There is no statistical difference in age of onset between male and female patients. The core manifestations of Chinese CRD patients are progressive cognitive decline, parkinsonism, and bilateral asymmetric white matter changes. Compared to men, women have more severe cognitive impairment and imaging changes. c.2381 T > C/p.I794T is a hotspot mutation in Chinese patients. © 2024 International Parkinson and Movement Disorder Society.

Clinical presentation and diagnosis of adult-onset leukoencephalopathy with axonal spheroids and pigmented glia: a literature analysis of case studies.

Because adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare, rapidly progressive, debilitating, and ultimately fatal neurodegenerative disease, a rapid and accurate diagnosis is critical. This analysis examined the frequency of initial misdiagnosis of ALSP via comprehensive review of peer-reviewed published cases. Data were extracted from a MEDLINE search via PubMed (January 1, 1980, through March 22, 2022) from eligible published case reports/series for patients with an ALSP diagnosis that had been confirmed by testing for the colony-stimulating factor-1 receptor gene (CSF1R) mutation. Patient demographics, clinical symptoms, brain imaging, and initial diagnosis data were summarized descriptively. Categorical data for patient demographics, symptoms, and brain imaging were stratified by initial diagnosis category to test for differences in initial diagnosis based on each variable. Data were extracted from a cohort of 291 patients with ALSP from 93 published case reports and case series. Mean (standard deviation) age of symptom onset was 43.2 (11.6) years. A family history of ALSP was observed in 59.1% of patients. Cognitive impairment (47.1%) and behavioral and psychiatric abnormalities (26.8%) were the most frequently reported initial symptoms. Of 291 total cases, an accurate initial diagnosis of ALSP was made in 72 cases (24.7%) and the most frequent initial misdiagnosis categories were frontotemporal dementia (28 [9.6%]) and multiple sclerosis (21 [7.2%]). Of the 219 cases (75.3%) that were initially mis- or undiagnosed, 206 cases (94.1%) were later confirmed as ALSP by immunohistology, imaging, and/or genetic testing; for the remaining 13 cases, no final diagnosis was reported. Initial diagnosis category varied based on age, family history, geographic region, mode of inheritance, and presenting symptoms of pyramidal or extrapyramidal motor dysfunction, behavioral and psychiatric abnormalities, cognitive impairment, and speech difficulty. Brain imaging abnormalities were common, and initial diagnosis category was significantly associated with white matter hyperintensities, white matter calcifications, and ventricular enlargement. In this literature analysis, ALSP was frequently misdiagnosed. Improving awareness of this condition and distinguishing it from other conditions with overlapping presenting symptoms is important for timely management of a rapidly progressive disease such as ALSP.

Gene Expression Levels of CSF-1 and CSF-1R Endometrial under The Influence of Prolactin Level in Unexplained Miscarriage: A Case-Control Study.

Hormones such as prolactin, by influencing expression of the endometrial genes, play a pivotal role in embryo implantation and development. The present study aimed to evaluate serum level of prolactin and its effect on altering expression level of colony-stimulating factor-1 (CSF-1) and colony-stimulating factor-1 receptor (CSF-1R) genes in endometrial tissue during in vitro fertilization (IVF) pregnancy in the infertile women and recurrent pregnancy loss (RPL), compared to fertile women, who lost their pregnancies at gestational age <20 weeks. In this case-control study, 40 infertile women, 40 IVF pregnant women with RPL and 40 fertile women who lost their pregnancies at <20 weeks of gestation for unknown reasons were selected. Prolactin serum level was assessed using ELISA technique and expression of CSF-1 and CSF-1R genes was determined in endometrial tissue, using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Mean prolactin level of the infertile group was 24.38 ± 1.43 ng/mL and it had statistically significant relationship with the fertile group (P<0.001). Expression level of the CSF-1 and CSF-1R genes were higher in the fertile than infertile groups by 2.88 times (P<0.0001) and 2.64 times (P<0.0001), while it was respectively 2.28 (P<0.0001) and 1.69 (P<0.0001) times higher compared to the RPL group. Risk factors for pregnancy loss, such as aging, increased body mass index (BMI), smoking and diabetes caused decreasing changes in gene expression (CSF-1 and CSF-1R ) and the differences were statistically significant, except in the infertile group. The present study showed a significant relationship of CSF-1 and CSF-1R expression levels with pregnancy loss. Risk factors such as aging, obesity, smoking and diabetes decreased both genes expression levels.

Adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia caused by a novel mutation of CSF1R gene

AbstractBackgroundAdult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare autosomal dominant disorder caused by mutations in the colony‐stimulating factor 1 receptor (CSF1R) gene. As of 2022, more than 100 different CSF1R mutations were reported in patients with CSF1R‐related leukoencephalopathy.MethodIn this case report, we described ALSP in a previously healthy 46‐year‐old woman. The patient underwent detailed neurological examinations including cognitive assessment, brain magnetic resonance imaging (MRI) and whole‐exome sequencing.ResultThe patient manifested as memory impairment, poor interpersonal behavior and decreased verbal fluency. Brain MRI showed confluent white matter changes and atrophy of the corpus callosum. Whole‐exome sequencing identified a novel splice site mutation (C.1858 + 5G &gt; A) in intron 13 of the CSF1R gene, which has not been reported worldwide.ConclusionALSP has a wide range of clinical manifestations and genetic heterogeneity. It should be considered when diagnosing rapidly progressive dementia with or without motor impairment. We recommend biopsy or genetic testing in these patients to avoid misdiagnosis and delayed diagnosis. We will continue to monitor this family in the future to improve our understanding of ALSP, so as to correctly diagnose ALSP in clinic and provide clinical data for better research on the pathogenesis and treatment of this disease.

Novel c.2654+1G&gt;A mutation in the CSF1R gene in a family with CSF1R‐microglial encephalopathy

AbstractBackgroundThe colony‐stimulating factor‐1 receptor (CSF1R) is a transmembrane tyrosine kinase receptor that is mainly expressed in the brain‐resident microglia. Thus, microglial dysfunction due to CSF1R mutation may play a primary and pivotal role in the pathogenesis of CSF1R‐microglial encephalopathy. Neither the functional consequences of all known CSF1R mutations nor the full genetic spectrum of mutations causing CSF1R‐microglial encephalopathy have been fully elucidated. We aimed to describe a novel heterozygous splicing variant of the CSF1R gene that caused CSF1R‐microglial encephalopathy in a Han Chinese family.MethodThe demographic data, detailed medical history, and clinical manifestations were collected from a family with CSF1R‐microglial encephalopathy. Some family members also underwent neuropsychological evaluation, structural and functional magnetic resonance imaging (MRI), and whole‐exome sequence analyses.ResultFour generations of this family, including 27 members, presented with a medical history of a dominant hereditary pattern (Figure 1). Seven of these 27 individuals had died, while five presented with similar cognitive impairments clinically, including the proband, and his sister, father, uncle, and grandmother during their life. Brain MRI of the proband (Figure 2) and his sister (Figure 3) depicted symmetric confluent and diffuse deep white matter changes, atrophy of the frontoparietal lobes, and thinning of the corpus callosum. The brother of the proband remained asymptomatic, and the structural brain MRI only revealed minimal white matter changes; however, pseudo‐continuous arterial spin labeling (pCASL) demonstrated marked reduction in the cerebral blood flow (CBF) in the bilateral deep white matter and corpus callosum (Figure 4). Whole‐exome sequencing was performed for seven family members, which identified a novel splice‐site heterozygous mutation (c.2319+1C&gt;A) in intron 20 of the CSF1R gene in four members (Figure 5).ConclusionWe identified a novel splicing mutation (c.2319+1C&gt;A) in intron 20 of CSF1R as the cause of CSF1R‐microglial encephalopathy in a Han Chinese family, which broadens the genetic spectrum of CSF1R‐microglial encephalopathy. We opine that clinically feasible pCASL techniques may be more sensitive to the alterations in CBF of associated with microglial density and cellular changes. This study highlights the potential value of pCASL techniques to improve the clinical diagnostic accuracy of CSF1R‐microglial encephalopathy.

Adult-Onset Leukoencephalopathy with Axonal Spheroid and Pigmented Glia: Different Histological Spectrums Presented in Autopsy Cases of Siblings and a Surgical Case of Stereotactic Biopsy

Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia encompasses hereditary diffuse leukoencephalopathy with axonal spheroids and pigmented orthochromatic leukodystrophy. We describe the clinicopathological and genetic findings of three patients with this disorder. All patients presented with dysarthria, with or without cognitive decline. The first and second patients were siblings who died of the disease at ages 42 and 54, respectively, while the third patient has been bedridden. Brain magnetic resonance imaging revealed T2 hyperintensities in the subcortical and periventricular white matter. Pathological diagnosis was established by brain autopsy in cases 1 and 2, and a stereotactic brain biopsy in case 3, followed by genetic analysis of colony stimulating factor-1 receptor gene. A heterozygous c.2345G > A (p.R782H) variant was identified in the autopsy-proven cases, and a c.1765G > A (p.G589R) variant in the biopsy-proven case. Postmortem examination revealed severe white matter degeneration involving the bilateral frontoparietal lobes, but sparing the subcortical U-fibers. All cases revealed widespread loss of myelinated axons in the white matter lesions; however, axonal spheroids and pigmented macrophages were abundant in cases 1 and 3 and much less in case 2. Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia should be considered in patients with presenile dementia and diffuse white matter lesions.

Donor CSF3R with the rs3917980A/G or G/G genotype is correlated with better leukemia-free survival after allogenic hematopoietic stem cell transplantation.

Polymorphisms in the granulocyte colony-stimulating factor receptor gene (GCSFR, CSF3R) have been reported to be associated with peripheral blood stem cell enrichment and hematological diseases. The aim of our study was to investigate the effects of donor CSF3R allelic polymorphisms on the outcomes of allogeneic stem cell transplantation. A total of 273 patients who were diagnosed with hematological diseases and treated with allogeneic hematopoietic stem cell transplantation(allo-HSCT) were enrolled in this study. Single-nucleotide polymorphisms in CSF3R were genotyped by targeted next-generation sequencing. There were six types of CSF3R genotypes with percentages over 1%. LFS and OS analyses showed that recipients receiving grafts from healthy donors with a rs3917980 G/G or A/G genotype had higher LFS rates than those receiving grafts from donors carrying a rs22754272 T/C genotype and the double-negative group (p = 0.036). Univariate cox analysis showed that donor CSF3R with the rs2275472 T/C genotype was associated with higher transplantation-related mortality (TRM) rates (HR = 2.853, 95% CI: 1.405-5.792, p = 0.00371) and lower rates of leukemia-free survival (LFS) (HR = 1.846; 95% CI: 1.018-3.347, p = 0.0435). In addition, donor CSF3R with the rs3917980G/G or A/G genotype was associated with better overall survival (OS) rates (HR = 0.560, 95% CI: 0.3162-0.9916, p = 0.047) and lower TRM rates (HR = 0.497, 95% CI: 0.2628-0.9397, p = 0.0315). Furthermore, multivariate cox analysis found that rs2275472 T/C genotype was an independent risk factors for TRM rates (HR = 3.210, 95% CI: 1.573-6.55, p = 0.001), while no statistical difference was found between rs3917980G/G or A/G genotype and clinical outcomes. Our findings demonstrate the important prognostic value of genetic variations in donor CSF3R to predict clinical outcomes in patients undergoing allo-HSCT.

Abstract 1648: Evaluation of therapeutic drug candidates using a novel humanized B-hCSF1/hCSF1R mouse model

Abstract An often rate-limiting step for cancer immunotherapy is drug development. The generation of humanized mouse models can be used to assess the clinical utility of new drugs earlier in the discovery process. Tumor-associated macrophages (TAMs) represent an emerging therapeutic target, specifically high expression of the colony-stimulating factor 1 receptor (CSF1R) protein on tumors and TAMs facilitate a tumor permissive environment. Previous reports have demonstrated that blockade of the CSF1/CSF1R pathway reduced and reprogrammed intra-tumoral CSF1R+ TAMs, altogether alleviating immune suppression. To evaluate preclinical efficacy and toxicity of CSF1R targeted therapeutic candidates, Biocytogen has successfully generated a double humanized B-hCSF1/hCSF1R mouse model. The full-length encoding sequence of mouse Csf1 and the extracellular domain of Csf1r were replaced by human CSF1 and CSF1R genes, respectively. Evaluation of CSF1 and CSF1R protein expression in homozygous B-hCSF1/hCSF1R mice (H/H) was confirmed by ELISA and flow cytometry analysis. We next performed an in vivo efficacy screening study using genetically modified hCSF1 or wild-type MC38 cells inoculated into B-hCSF1/hCSF1R (H/H) mice and observed that anti-human CSF1R antibodies or combination therapy of anti-mouse PD-L1 and anti-human CSF1R antibodies were effective in controlling tumor growth. Our combined studies illustrate that Biocytogen’s novel B-hCSF1/hCSF1R mice offer a promising model for in vivo validation of CSF1 and CSF1R antibody therapeutics. Citation Format: Ruili Lyu, Shujin Zhang, Rebecca Soto, Suman Zhao, Chonghui Liu, Luke (Zhaoxue) Yu. Evaluation of therapeutic drug candidates using a novel humanized B-hCSF1/hCSF1R mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1648.

Four Swedish cases of CSF1R-related leukoencephalopathy: Visualization of clinical phenotypes.

Colony stimulating factor 1 receptor (CSF1R)‐related leukoencephalopathy is a rare, genetic disease caused by heterozygous mutations in the CSF1R gene with rapidly progressive neurodegeneration, behavioral, cognitive, motor disturbances.ObjectiveTo describe four cases of CSF1R‐related leukoencephalopathy from three families with two different pathogenic mutations in the tyrosine kinase domain of CSF1R and to develop an integrated presentation of inter‐individual diversity of clinical presentations.MethodsThis is an observational study of a case series. Patients diagnosed with CSF1R encephalopathy were evaluated with standardized functional estimation scores and subject to analysis of cerebrospinal fluid biomarkers. Brain computed tomography (CT) and magnetic resonance imaging (MRI) were evaluated. We performed a functional phosphorylation assay to confirm the dysfunction of mutated CSF1R protein.ResultsTwo heterozygous missense mutations in the CSF1R gene were identified, c.2344C>T; p.Arg777Trp and c.2329C>T; p.Arg782Cys. A phosphorylation assay in vitro showed markedly reduced autophosphorylation in cells expressing mutations. According to ACMG criteria, both mutations were pathogenic. A radiological investigation revealed typical white matter lesions in all cases. There was inter‐individual diversity in the loss of cognitive, motor‐neuronal, and extrapyramidal functions.ConclusionsIncluding the present cases, currently three CSF1R mutations are known in Sweden. We present a visualization tool to describe the clinical diversity, with potential use for longitudinal follow‐up for this and other leukoencephalopathies.

Novel CSF1R variant in adult-onset leukoencephalopathy masquerading as frontotemporal dementia: a follow-up study

ABSTRACT Adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare white matter degenerative disease manifesting as progressive cognitive decline, pyramidal, and extrapyramidal features resulting from mutations in the colony-stimulating factor-1 receptor (CSF1R) gene. We describe a sporadic case of a young man who developed five months history of progressive cognitive decline with predominant neuropsychiatric symptoms, suggestive of frontotemporal dementia. Brain magnetic resonance imaging (MRI) showed bilateral frontotemporal atrophy, high signal intensities in frontal and high parietal deep white matter with persistent diffusion restriction on follow-up imaging. Genetics showed a novel heterozygous mutation in CSF1R gene confirming the diagnosis of ALSP. Being a rare disease, and given its particular adult-onset presentation especially presenile cognitive impairment, it can pose a unique diagnostic challenge. The study highlights the importance of recognizing the disease early and broadens the clinical, genetic, and imaging spectrum of CSF1R gene mutation.

Characterization of a novel CSF1R mutation causing hereditary diffuse leukoencephalopathy with spheroids in a case presenting with young-onset dementia

ObjectiveThis poster aims to report an unregistered mutation CSF1R gene in a patient presenting young-onset dementia.Hypothesis: Novel heterozygous deletion–insertion mutation in the Colony-Stimulating Factor 1 Receptor (CSF1R) gene is linked to a case of hereditary diffuse leukoencephalopathy with spheroids (HDLS), presenting with young-onset dementia.BackgroundCSF1R mediates proliferation, differentiation, and survival of monocytes/ macrophages and microglia. Pathogenic variants in the CSF1R gene cause autosomal dominant diffuse hereditary leukoencephalopathy with spheroids characterized by variable behavioural, cognitive, and motor changes, usually presenting with young-onset dementia. The average lifespan after the start of the symptoms is often 6 years.Case reportMolecular genetic analysis of whole-exome sequencing (WES) was carried out for a 49-year-old male patient presenting with rapid cognitive decline, behavioural symptoms and impaired sphincteric control.DiscussionWES identified the heterozygous deletion–insertion variant c.2356_2357delinsAC p.(Leu786Thr) (chr5:149435867-49435868; hg19) in the CSF1R gene. To the best of our knowledge the variant has not been described in the literature so far (HGMD 2019.3). No allele frequencies in the general population have been documented.ConclusionWe believe that we have identified a novel mutation in the CSF1R gene. This mutation is likely to be linked to this patient presenting with young-onset dementia.

A novel mutation in CSF1R associated with hereditary diffuse leukoencephalopathy with spheroids.

Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal-dominant disorder with high penetrance characterized by progressive cognitive and motor dysfunction. The objective of the study was to describe a new variant of the colony stimulating factor-1 receptor (CSF1R) gene causing HDLS in a Chinese family. Physical examinations, laboratory tests, structural neuroimaging studies, and whole-exome sequence analysis were carried out. Three patients in this family exhibited typical manifestations of HDLS, including progressive cognitive impairment, language and motor dysfunctions, and urinary and bowel incontinence. Genetic analysis identified a heterozygous missense mutation (c.2264T>C, p.L755P) in exon 17 of the CSF1R gene that cosegregated with the HDLS phenotype in an autosomal-dominant pattern. Brain MRI of the proband and her father showed diffuse white matter changes. The proband's 10-year-old son, a gene carrier, remains clinically asymptomatic at present. Our findings identify a novel missense mutation, p.L755P, in the CSF1R gene within a Chinese family with autosomal-dominant HDLS and broaden the genetic spectrum of CSF1R-associated HDLS.

Integrative Statistics, Machine Learning and Artificial Intelligence Neural Network Analysis Correlated CSF1R with the Prognosis of Diffuse Large B-Cell Lymphoma

Tumor-associated macrophages (TAMs) of the immune microenvironment play an important role in the Diffuse Large B-cell Lymphoma (DLBCL) pathogenesis. This research aimed to characterize the expression of macrophage colony-stimulating factor 1 receptor (CSF1R) at the gene and protein level in correlation with survival. First, the immunohistochemical expression of CSF1R was analyzed in a series of 198 cases from Tokai University Hospital and two patterns of histological expression were found, a TAMs, and a diffuse B-lymphocytes pattern. The clinicopathological correlations showed that the CSF1R + TAMs pattern associated with a poor progression-free survival of the patients, disease progression, higher MYC proto-oncogene expression, lower MDM2 expression, BCL2 translocation, and a MYD88 L265P mutation. Conversely, a diffuse CSF1R + B-cells pattern was associated with a favorable progression-free survival. Second, the histological expression of CSF1R was also correlated with 10 CSF1R-related markers including CSF1, STAT3, NFKB1, Ki67, MYC, PD-L1, TNFAIP8, IKAROS, CD163, and CD68. CSF1R moderately correlated with STAT3, TNFAIP8, CD68, and CD163 in the cases with the CSF1R + TAMs pattern. In addition, machine learning modeling predicted the CSF1R immunohistochemical expression with high accuracy using regression, generalized linear, an artificial intelligence neural network (multilayer perceptron), and support vector machine (SVM) analyses. Finally, a multilayer perceptron analysis predicted the genes associated with the CSF1R gene expression using the GEO GSE10846 DLBCL series of the Lymphoma/Leukemia Molecular Profiling Project (LLMPP), with correlation to the whole set of 20,683 genes as well as with an immuno-oncology cancer panel of 1790 genes. In addition, CSF1R positively correlated with SIRPA and inversely with CD47. In conclusion, the CSF1R histological pattern correlated with the progression-free survival of the patients of the Tokai series, and predictive analytics is a feasible strategy in DLBCL.

Relationships between novel nucleotide variants within the colony-stimulating factor 1 receptor (CSF1R) gene and mastitis indicators in sheep

Colony-stimulating factor 1 receptor (CSF1R) plays an important role in the process of innate immunity and inflammation, thus it was hypothesized that the CSF1R gene might affect the occurrence of mammalian mastitis. The purpose of this study was to investigate the association between nucleotide variations of CSF1R gene and mastitis in Australian white sheep (AUWs). Two indel variants (Intron5-27 bp and Intron5-22 bp) within the CSF1R gene have been found in AUWs. The Chi-square test for different mastitis symptoms demonstrated that individuals without symptoms of mastitis had higher ‘I’ allele frequencies and ‘II’ genotype frequencies (p < 0.01). We found strong correlation between mastitis and lactation score through Pearson correlation analysis. Therefore, we also analyzed the relationship between the two indel loci and lactation, we found that the lactation ability of individuals with type II was stronger than that of DD genotype at the Intron5-22 bp (p < 0.05). Additionally, we found that the combined genotype of the two loci was significantly associated with mastitis (p < 0.01). These findings indicated that CSF1R mutations were significantly associated with mastitis, and could affect lactation performance, suggesting that two deletion sites could be used as the effective molecular markers against mastitis in sheep breeding.

Lipid Pathology of the Corpus Callosum in Schizophrenia and the Potential Role of Abnormal Gene Regulatory Networks with Reduced Microglial Marker Expression.

Structural changes in the corpus callosum have been reported in schizophrenia; however, the underlying molecular mechanism remains unclear. As the corpus callosum is high in lipid content, we analyzed the lipid contents of the corpora callosa from 15 patients with schizophrenia and 15 age- and sex-matched controls using liquid chromatography coupled to tandem mass spectrometry and identified lipid combinations associated with schizophrenia. Real-time quantitative polymerase chain reaction analyses using extended samples (schizophrenia, n = 95; control, n = 91) showed low expression levels of lipid metabolism-related genes and their potential upstream transcription factors in schizophrenia. Subsequent pathway analysis identified a gene regulatory network where nuclear factor of activated T cells 2 (NFATC2) is placed most upstream. We also observed low gene expression levels of microglial markers, inflammatory cytokines, and colony-stimulating factor 1 receptor (CSF1R), which is known to regulate the density of microglia, in the corpus callosum in schizophrenia. The interactions between CSF1R and several genes in the presently identified gene network originating from NFATC2 have been reported. Collectively, this study provides evidence regarding lipid abnormalities in the corpora callosa of patients with schizophrenia and proposes the potential role of impaired “NFATC2-relevant gene network-microglial axis” as its underlying mechanism.

Primary Alcohol-Activated Human and Mouse Hepatic Stellate Cells Share Similarities in Gene-Expression Profiles.

Alcoholic liver disease (ALD) is a leading cause of cirrhosis in the United States, which is characterized by extensive deposition of extracellular matrix proteins and formation of a fibrous scar. Hepatic stellate cells (HSCs) are the major source of collagen type 1 producing myofibroblasts in ALD fibrosis. However, the mechanism of alcohol‐induced activation of human and mouse HSCs is not fully understood. We compared the gene‐expression profiles of primary cultured human HSCs (hHSCs) isolated from patients with ALD (n = 3) or without underlying liver disease (n = 4) using RNA‐sequencing analysis. Furthermore, the gene‐expression profile of ALD hHSCs was compared with that of alcohol‐activated mHSCs (isolated from intragastric alcohol‐fed mice) or CCl4‐activated mouse HSCs (mHSCs). Comparative transcriptome analysis revealed that ALD hHSCs, in addition to alcohol‐activated and CCl4‐activated mHSCs, share the expression of common HSC activation (Col1a1 [collagen type I alpha 1 chain], Acta1 [actin alpha 1, skeletal muscle], PAI1 [plasminogen activator inhibitor‐1], TIMP1 [tissue inhibitor of metalloproteinase 1], and LOXL2 [lysyl oxidase homolog 2]), indicating that a common mechanism underlies the activation of human and mouse HSCs. Furthermore, alcohol‐activated mHSCs most closely recapitulate the gene‐expression profile of ALD hHSCs. We identified the genes that are similarly and uniquely up‐regulated in primary cultured alcohol‐activated hHSCs and freshly isolated mHSCs, which include CSF1R (macrophage colony‐stimulating factor 1 receptor), PLEK (pleckstrin), LAPTM5 (lysosmal‐associated transmembrane protein 5), CD74 (class I transactivator, the invariant chain), CD53, MMP9 (matrix metallopeptidase 9), CD14, CTSS (cathepsin S), TYROBP (TYRO protein tyrosine kinase‐binding protein), and ITGB2 (integrin beta‐2), and other genes (compared with CCl4‐activated mHSCs). Conclusion: We identified genes in alcohol‐activated mHSCs from intragastric alcohol‐fed mice that are largely consistent with the gene‐expression profile of primary cultured hHSCs from patients with ALD. These genes are unique to alcohol‐induced HSC activation in two species, and therefore may become targets or readout for antifibrotic therapy in experimental models of ALD.

CSF1R-related leukoencephalopathy: A major player in primary microgliopathies.

Since the discovery of CSF1R gene mutations in families with hereditary diffuse leukoencephalopathy with spheroids in 2012, more than 70 different mutations have been identified around the world. Through the analyses of mutation carriers, CSF1R-related leukoencephalopathy has been distinctly characterized clinically, radiologically, and pathologically. Typically, patients present with frontotemporal dementia-like phenotype in their 40s-50s, accompanied by motor symptoms, including pyramidal and extrapyramidal signs. Women tend to develop the clinical symptoms at a younger age than men. On brain imaging, in addition to white matter abnormalities, thinning of the corpus callosum, diffusion-restricted lesions in the white matter, and brain calcifications are hallmarks. Primary axonopathy followed by demyelination was suggested by pathology. Haploinsufficiency of colony-stimulating factor-1 receptor (CSF1R) is evident in a patient with a frameshift mutation, facilitating the establishment of Csf1r haploinsufficient mouse model. These mice develop clinical, radiologic, and pathologic phenotypes consistent with those of human patients with CSF1R mutations. In vitro, perturbation of CSF1R signaling is shown in cultured cells expressing mutant CSF1R. However, the underlying mechanisms by which CSF1R mutations selectively lead to white matter degeneration remains to be elucidated. Given that CSF1R mainly expresses in microglia, CSF1R-related leukoencephalopathy is representative of primary microgliopathies, of which microglia have a pivotal and primary role in pathogenesis. In this review, we address the current knowledge of CSF1R-related leukoencephalopathy and discuss the putative pathophysiology, with a focus on microglia, as well as future research directions.

Colony stimulating factor-1 receptor promotes proliferation, migration and invasion in the human nasopharyngeal carcinoma 6-10B cell line via the phosphoinositide 3-kinase/Akt pathway.

The present study aimed to investigate the effects of colony-stimulating factor-1 receptor (CSF-1R) on proliferation, migration and invasion in the human nasopharyngeal carcinoma (NPC) 6-10B cell line, and to investigate the possible underlying mechanisms. Using a lentiviral transfection method, a virus carrying the CSF-1R gene was transfected into 6-10B cells. The expression of CSF-1R was then detected by reverse transcription-quantitative polymerase chain reaction and western blot analysis, and was revealed to be markedly enhanced in 6-10B cells. Subsequently, an MTT assay was performed to assess cell proliferative ability, and flow cytometric analysis was utilized to measure the apoptotic rate of the cells. Wound healing and Transwell assays were also performed to observe cell migration and invasion capabilities. Additionally, western blot analysis was used to detect the protein expression of the proliferation and apoptosis signaling factors cyclin D1, B-cell lymphoma 2, Bcl-2-associated X protein, and phosphorylated and total extracellular protein kinase B (Akt/PKB) in 6-10B cells. The results showed that CSF-1R overexpression promoted the proliferation, migration and invasion of the 6-10B cells. The corresponding mechanism may be associated with activation of the phosphoinositide 3-kinase/Akt pathway, which promotes cell survival and proliferation. These results indicated a potential molecular target for the treatment of NPC.

Chemo-genomic interrogation of CEBPA mutated AML reveals recurrent CSF3R mutations and subgroup sensitivity to JAK inhibitors

AbstractIn this study, we analyzed RNA-sequencing data of 14 samples characterized by biallelic CEBPA (CEBPAbi) mutations included in the Leucegene collection of 415 primary acute myeloid leukemia (AML) specimens, and describe for the first time high frequency recurrent mutations in the granulocyte colony-stimulating factor receptor gene CSF3R, which signals through JAK-STAT proteins. Chemical interrogation of these primary human specimens revealed a uniform and specific sensitivity to all JAK inhibitors tested irrespective of their CSF3R mutation status, indicating a general sensitization of JAK-STAT signaling in this leukemia subset. Altogether, these results identified the co-occurrence of mutations in CSF3R and CEBPA in a well-defined AML subset, which uniformly responds to JAK inhibitors and paves the way to personalized clinical trials for this disease.

A family with hereditary diffuse leukoencephalopathy with spheroids caused by a novel c.2442 + 2T > C mutation in the CSF1R gene

Clinical phenotypes of hereditary diffuse leukoencephalopathy with spheroids (HDLS), a familial progressive neurodegenerative disorder affecting the white matter of the brain, are heterogenous and may include behavioral and personality changes, memory impairment, parkinsonism, seizure, and spasticity. Thus, HDLS is frequently unrecognized and misdiagnosed. Heterozygous mutations located within the kinase domain of the gene encoding the colony-stimulating factor 1 receptor (CSF1R), a cell surface receptor with key roles in development and innate immunity, have been shown in HDLS. These different gene mutations may be related to the various clinical phenotypes. We report here a newly identified family with HDLS harboring a mutation in the CSF1R gene. We examined clinical and neuropathological features in three members of this family. These patients presented with affective incontinence, memory impairment, and executive dysfunction at onset, and revealed nonfluent aphasia, parkinsonism, and seizure as the disease progressed. We identified a novel CSF1R splice site mutation (c.2442+2T>C) in intron 18 for two of the patients. MRI of these patients revealed progressive, frontotemporal-predominant, confluent leukoencephalopathy. We also observed severe myelin loss, axonal degeneration, and abundant axonal spheroids, astrocytes, and microglia in the cerebral white matter, consistent with HDLS neuropathological features. Additionally, we identified atypical neuropathological findings for HDLS, including neuronal loss and gliosis with ballooned neurons and central chromatolysis in the frontal cortex and hippocampus. This report provides further evidence for the clinical and neuropathological heterogeneity of HDLS.