Molecule Information

General Information of the Molecule (ID: Mol01838)

• Name: Granulocyte colony-stimulating factor receptor (CSF3R) ,Homo sapiens
• Synonyms: Granulocyte colony-stimulating factor receptor; G-CSF receptor; G-CSF-R; CD antigen CD114; CSF3R; GCSFR
• Molecule Type: Protein
• Gene Name: CSF3R
• Gene ID: 1441
• Location: chr1:36,466,043-36,483,278[-]
• Sequence:
  MARLGNCSLTWAALIILLLPGSLEECGHISVSAPIVHLGDPITASCIIKQNCSHLDPEPQ
  ILWRLGAELQPGGRQQRLSDGTQESIITLPHLNHTQAFLSCCLNWGNSLQILDQVELRAG
  YPPAIPHNLSCLMNLTTSSLICQWEPGPETHLPTSFTLKSFKSRGNCQTQGDSILDCVPK
  DGQSHCCIPRKHLLLYQNMGIWVQAENALGTSMSPQLCLDPMDVVKLEPPMLRTMDPSPE
  AAPPQAGCLQLCWEPWQPGLHINQKCELRHKPQRGEASWALVGPLPLEALQYELCGLLPA
  TAYTLQIRCIRWPLPGHWSDWSPSLELRTTERAPTVRLDTWWRQRQLDPRTVQLFWKPVP
  LEEDSGRIQGYVVSWRPSGQAGAILPLCNTTELSCTFHLPSEAQEVALVAYNSAGTSRPT
  PVVFSESRGPALTRLHAMARDPHSLWVGWEPPNPWPQGYVIEWGLGPPSASNSNKTWRME
  QNGRATGFLLKENIRPFQLYEIIVTPLYQDTMGPSQHVYAYSQEMAPSHAPELHLKHIGK
  TWAQLEWVPEPPELGKSPLTHYTIFWTNAQNQSFSAILNASSRGFVLHGLEPASLYHIHL
  MAASQAGATNSTVLTLMTLTPEGSELHIILGLFGLLLLLTCLCGTAWLCCSPNRKNPLWP
  SVPDPAHSSLGSWVPTIMEEDAFQLPGLGTPPITKLTVLEEDEKKPVPWESHNSSETCGL
  PTLVQTYVLQGDPRAVSTQPQSQSGTSDQVLYGQLLGSPTSPGPGHYLRCDSTQPLLAGL
  TPSPKSYENLWFQASPLGTLVTPAPSQEDDCVFGPLLNFPLLQGIRVHGMEALGSF
• Function: Receptor for granulocyte colony-stimulating factor (CSF3), essential for granulocytic maturation. Plays a crucial role in the proliferation, differientation and survival of cells along the neutrophilic lineage. In addition it may function in some adhesion or recognition events at the cell surface.
• Uniprot ID: CSF3R_HUMAN
• Ensembl ID: ENSG00000119535
• HGNC ID: HGNC:2439

Kingdom: Metazoa
Phylum: Chordata
Class: Mammalia
Order: Primates
Family: Hominidae
Genus: Homo
Species: Homo sapiens

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Ruxolitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [1]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Ruxolitinib
• Molecule Alteration: Missense mutation; p.N610H (c.1828A>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: C57/BL6 mouse model; Mus musculus
• Experiment for Molecule Alteration: Sanger genomic DNA sequencing assay
• Experiment for Drug Resistance: MTS assay

Disease Class: Solid tumour/cancer [2]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Ruxolitinib
• Molecule Alteration: Missense mutation; p.T640N (c.1919C>A)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 293T17 cells; Kidney; Homo sapiens (Human); CVCL_0063
• In Vivo Model: Balb/c bone marrow transplantation mouse model; Mus musculus
• Experiment for Molecule Alteration: Sanger sequencing assay; Western blotting analysis
• Experiment for Drug Resistance: Cytokine-independent growth assay

Disease Class: Atypical chronic myeloid leukemia [3]

• Sensitive Disease: Atypical chronic myeloid leukemia [ICD-11: 2A41.1]
• Sensitive Drug: Ruxolitinib
• Molecule Alteration: Missense mutation; p.T615A (c.1843A>G)
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: The missense mutation p.T615A (c.1843A>G) in gene CSF3R cause the sensitivity of Ruxolitinib by unusual activation of pro-survival pathway

Disease Class: Chronic myeloid leukemia [4]

• Sensitive Disease: Chronic myeloid leukemia [ICD-11: 2A20.0]
• Sensitive Drug: Ruxolitinib
• Molecule Alteration: Missense mutation; p.T618I (c.1853C>T)
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vivo Model: BALB/C nude mouse xenograft model; Mus musculus

Disease Class: Atypical chronic myeloid leukemia [3]

• Sensitive Disease: Atypical chronic myeloid leukemia [ICD-11: 2A41.1]
• Sensitive Drug: Ruxolitinib
• Molecule Alteration: Missense mutation; p.T618I (c.1853C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• Experiment for Molecule Alteration: Direct sequencing assay
• Mechanism Description: The missense mutation p.T618I (c.1853C>T) in gene CSF3R cause the sensitivity of Ruxolitinib by unusual activation of pro-survival pathway

Disease Class: Solid tumour/cancer [1]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Ruxolitinib
• Molecule Alteration: Missense mutation; p.N610S (c.1829A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: C57/BL6 mouse model; Mus musculus
• Experiment for Molecule Alteration: Sanger genomic DNA sequencing assay
• Experiment for Drug Resistance: MTS assay

Trametinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [1]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.N610S (c.1829A>G)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: C57/BL6 mouse model; Mus musculus
• Experiment for Molecule Alteration: Sanger genomic DNA sequencing assay
• Experiment for Drug Resistance: MTS assay

Disease Class: Solid tumour/cancer [1]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Trametinib
• Molecule Alteration: Missense mutation; p.N610H (c.1828A>C)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: C57/BL6 mouse model; Mus musculus
• Experiment for Molecule Alteration: Sanger genomic DNA sequencing assay
• Experiment for Drug Resistance: MTS assay

Preclinical Drug(s) 1 drug(s) in total

Ibrutinib/Ruxolitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Ibrutinib/Ruxolitinib
• Molecule Alteration: Nonsense; p.Q741* (c.2221C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: BTK signaling pathway; Inhibition; hsa04662
• Experiment for Drug Resistance: Trypan blue staining assay
• Mechanism Description: G-CSFR mutants showed abnormal kinetics of canonical STAT3, STAT5 and MAPK phosphorylation, and aberrant activation of Bruton's Tyrosine Kinase (Btk).

Disease Class: Solid tumour/cancer [5]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Ibrutinib/Ruxolitinib
• Molecule Alteration: Missense mutation; p.T618I (c.1853C>T)
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: BTK signaling pathway; Inhibition; hsa04662
• Experiment for Drug Resistance: Trypan blue staining assay
• Mechanism Description: G-CSFR mutants showed abnormal kinetics of canonical STAT3, STAT5 and MAPK phosphorylation, and aberrant activation of Bruton's Tyrosine Kinase (Btk).

Disease- and Tissue-specific Abundances of This Molecule

ICD Disease Classification 02

Chronic myeloid leukemia [ICD-11: 2A20]

Differential expression of molecule in resistant diseases

• The Studied Tissue: Whole blood
• The Specified Disease: Myelofibrosis
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 4.57E-03; Fold-change: -4.94E-01; Z-score: -1.30E+00
• The Studied Tissue: Whole blood
• The Specified Disease: Polycythemia vera
• The Expression Level of Disease Section Compare with the Healthy Individual Tissue: p-value: 1.69E-02; Fold-change: -2.12E-01; Z-score: -4.97E-01

References

• Ref 1: A Novel Germline Variant in CSF3R Reduces N-Glycosylation and Exerts Potent Oncogenic Effects in LeukemiaCancer Res. 2018 Dec 15;78(24):6762-6770. doi: 10.1158/0008-5472.CAN-18-1638. Epub 2018 Oct 22.
• Ref 2: The Colony-Stimulating Factor 3 Receptor T640N Mutation Is Oncogenic, Sensitive to JAK Inhibition, and Mimics T618IClin Cancer Res. 2016 Feb 1;22(3):757-64. doi: 10.1158/1078-0432.CCR-14-3100. Epub 2015 Oct 16.
• Ref 3: Oncogenic CSF3R mutations in chronic neutrophilic leukemia and atypical CMLN Engl J Med. 2013 May 9;368(19):1781-90. doi: 10.1056/NEJMoa1214514.
• Ref 4: The CSF3R T618I mutation causes a lethal neutrophilic neoplasia in mice that is responsive to therapeutic JAK inhibitionBlood. 2013 Nov 21;122(22):3628-31. doi: 10.1182/blood-2013-06-509976. Epub 2013 Sep 30.
• Ref 5: Time resolved quantitative phospho-tyrosine analysis reveals Bruton's Tyrosine kinase mediated signaling downstream of the mutated granulocyte-colony stimulating factor receptorsLeukemia. 2019 Jan;33(1):75-87. doi: 10.1038/s41375-018-0188-8. Epub 2018 Jul 5.