Time resolved quantitative phospho-tyrosine analysis reveals Bruton’s Tyrosine kinase mediated signaling downstream of the mutated granulocyte-colony stimulating factor receptors

Dwivedi, Pankaj; Muench, David E.; Wagner, Michael; Azam, Mohammad; Grimes, H. Leighton; Greis, Kenneth D.

doi:10.1038/s41375-018-0188-8

Cited by 53 publications

(52 citation statements)

References 32 publications

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“…The truncation mutations, which also occur in SCN, largely coexisted with membrane proximal or transmembrane CSF3R mutations as compound mutations . Mechanistically, the membrane proximal mutations prevent O ‐glycosylation of CSF3R resulting in increased active dimeric configuration, ligand‐independent receptor activation, and constitutive downstream signaling through JAK2 (and potentially Brutonʼs tyrosine kinase according to a recent report). On the other hand, receptor truncation involves a loss of negative regulatory motifs including the dileucine sorting motif, which plays a role in receptor internalization, and binding sites for the suppressor of cytokine signaling 3 (SOCS3) which targets the receptor for degradation .…”

Section: Molecular Pathogenesismentioning

confidence: 99%

Chronic neutrophilic leukemia: 2020 update on diagnosis, molecular genetics, prognosis, and management

2019

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Disease overview: Chronic neutrophilic leukemia (CNL) is a rare, often aggressive myeloproliferative neoplasm (MPN) defined by persistent mature neutrophilic leukocytosis, bone marrow granulocyte hyperplasia, and frequent hepatosplenomegaly. The seminal discovery of oncogenic driver mutations in colony-stimulating factor 3 receptor (CSF3R) in the majority of patients with CNL in 2013 anchored a new scientific framework, deepening our understanding of its molecular pathogenesis, providing a diagnostic biomarker, and rationalizing the use of pharmacological targeting. Diagnostic criteria: In 2016, the World Health Organization (WHO) included the presence of activating CSF3R mutations as a central diagnostic feature of CNL. Other criteria include leukocytosis of ≥25 × 10 9 /L comprising >80% neutrophils with <10% circulating precursors and rare blasts, and absence of dysplasia or monocytosis, while not fulfilling criteria for other MPN.Disease updates: Increasingly comprehensive genetic profiling of CNL has disclosed a complex genomic landscape and additional prognostically relevant mutational combinations. Though prognostic determination and therapeutic decision-making remain challenging, emerging data on prognostic markers and the use of newer therapeutic agents, such as JAK inhibitors, are helping to define state-of-the-art management in CNL.

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Section: Molecular Pathogenesismentioning

confidence: 99%

Chronic neutrophilic leukemia: 2020 update on diagnosis, molecular genetics, prognosis, and management

2019

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“…[1][2][3][4] Previous studies have reported somatic mutations in CSF3R cytoplasmic domain (most frequent Q741x) in the SCN patient cohorts undergoing prolong G-CSF therapy. [5] In our previous studies, [6,7] we have presented phosphoproteomics datasets pointing to aberrant signaling through Bruton's tyrosine kinase (BTK) [6] and many of other phospho-Ser/Thr signaling changes between the normal and mutated G-CSFRs. [7] Aberrant activation of BTK was validated in mouse as well as human models.…”

Section: Doi: 101002/prca201900144mentioning

confidence: 99%

“…[7] Aberrant activation of BTK was validated in mouse as well as human models. [6] Furthermore, a significant reduction in the overall leukemic potential of the mutated G-CSFRs expressing primary cells were reported after ibrutinib (FDA approved BTK inhibitor) treatment. [6] However, the signaling mechanism of ibrutinib's action is not fully known.…”

Section: Doi: 101002/prca201900144mentioning

confidence: 99%

“…[6] Furthermore, a significant reduction in the overall leukemic potential of the mutated G-CSFRs expressing primary cells were reported after ibrutinib (FDA approved BTK inhibitor) treatment. [6] However, the signaling mechanism of ibrutinib's action is not fully known. Here we present a label-free sequential window acquisition of all theoretical fragment ion-mass spectrometry (SWATH-MS) [8,9] study analyzing global proteome changes in the WT, and truncated (Q741x) G-CSFRs in response with ibrutinib treatment.…”

Section: Doi: 101002/prca201900144mentioning

confidence: 99%

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SWATH‐Proteomics of Ibrutinib's Action in Myeloid Leukemia Initiating Mutated G‐CSFR Signaling

Dwivedi

Muench

Azam

et al. 2020

Proteomics Clinical Apps

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Purpose To evaluate cellular protein changes in response to treatment with an approved drug, ibrutinib, in cells expressing normal or mutated granulocyte‐colony stimulating factor receptor (G‐CSFR). G‐CSFR mutations are associated with some hematological malignancies. Previous studies show the efficacy of ibrutinib (a Bruton's tyrosine kinase inhibitor) in mutated G‐CSFR leukemia models but do not address broader signaling mechanisms. Experimental Design A label‐free quantitative proteomics workflow to evaluate the cellular effects of ibrutinib treatment is established. This includes three biological replicates of normal and mutated G‐CSFR expressed in a mouse progenitor cell (32D cell line) with and without ibrutinib treatment. Results The proteomics dataset shows about 1000 unique proteins quantified with nearly 400 significant changes (p value < 0.05), suggesting a highly dynamic network of cellular signaling in response to ibrutinib. Importantly, the dataset is very robust with coefficients of variation for quantitation at 13.0–20.4% resulting in dramatic patterns of protein differences among the groups. Conclusions and Clinical Relevance This robust dataset is available for further mining, hypothesis generation, and testing. A detailed understanding of the restructuring of the proteomics signaling cascades by ibrutinib in leukemia biology will provide new avenues to explore its use for other related malignancies.

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“…The expression of total 137 DEGs was shown in heatmap, which was shown the relative expression level of DEGs( Fig. 2A) [19][20]. Then the 137 DEGs were verified by the DEGs PPI network tool of STRING, which included 243 edges and 104 nodes.…”

Section: Ppi Network and Core Genes Analysismentioning

confidence: 99%

Genes co-related with poor prognosis of patients with lung cancer via bioinformatical approaches

Shi¹,

Han²,

Wang³

et al. 2020

Preprint

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Lung cancer is one of the most common malignant tumors with high mortality worldwide. Recently, researchers reported that molecular markers on lung cancer could be used as diagnostic and prognostic targets. However, these molecules were not ideal in specificity and high selectivity.Therefore, exploring more reliable biomarkers to improve the prognosis and clarify the underlying mechanism is urgently needed both for clinic and basic research. This study aimed to identify significant genes with poor prediction for lung cancer and their underlying mechanisms. Firstly, we used gene expression datasets available from GEO (Gene Expression Omnibus) database. There were 109 lung cancer samples and 27 normal samples in the selected datasets. First, DEGs (Different Expressed Gene set) of lung cancer and normal lung samples were screen out with GEO2R tool, and we displayed them by Venn diagram software and Heatmap. Secondly, we used DAVID (Database for Annotation, Visualization and Integrated Discovery) to analyze KEGG (Kyoto Encyclopedia of Gene and Genome) pathway and GO (Gene Ontology). Third, PPI (Protein-Protein Interaction) of these DEGs was conducted by Cytoscape with STRING (Search Tool for the Retrieval of Interacting Genes). Our results showed that the expression trends of 21 up-regulated genes and 116 down-regulated were similar in selected three datasets. Analyzed by MCODE (Molecular Complex Detection) plug-in, 11 up-regulated and 16 down-regulated genes were selected. To further verify gene expression differences, GEPIA (Gene Expression Profiling Interactive Analysis) was implemented and we found 26 of 27 genes were found differently expressed in lung cancer compared with normal lung tissues. Furthermore, Kaplan-Meier analysis was used and we found 23 of 26 genes for overall survival indicated much less survival time. At last, three genes, CDH5, CLDN5, PECAM1, were found to be significantly decreased in lung cancer tissue proved through re-analysis of DAVID, which mainly co-related with leukocyte transendothelial migration. In conclusion, three significant down-regulated deferentially expressed genes with poor prognosis on lung cancer were identified basing on integrated bioinformatical methods.These down-expressed genes may be as a potential prognosis targets for patients with lung cancer.

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Time resolved quantitative phospho-tyrosine analysis reveals Bruton’s Tyrosine kinase mediated signaling downstream of the mutated granulocyte-colony stimulating factor receptors

Cited by 53 publications

References 32 publications

Chronic neutrophilic leukemia: 2020 update on diagnosis, molecular genetics, prognosis, and management

Chronic neutrophilic leukemia: 2020 update on diagnosis, molecular genetics, prognosis, and management

SWATH‐Proteomics of Ibrutinib's Action in Myeloid Leukemia Initiating Mutated G‐CSFR Signaling

Genes co-related with poor prognosis of patients with lung cancer via bioinformatical approaches

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