Disease Information

General Information of the Disease (ID: DIS00574)

• Name: Epstein-Barr virus
• ICD: ICD-11: XN0R2

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Drug

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

Pomalidomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Protein cereblon (CRBN) [1]

• Resistant Disease: Epstein-barr virus (ebv) infection [ICD-11: XN0R2]
• Resistant Drug: Pomalidomide
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Daudi cells; Peripheral blood; Homo sapiens (Human); CVCL_0008
• In Vitro Model: Namalwa cells; Lymphoid; Homo sapiens (Human); CVCL_0067
• In Vitro Model: EBV-negative BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: EBV-positive BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: BCBL-1 cells; Peritoneal fluid; Homo sapiens (Human); CVCL_0165
• In Vitro Model: JSC-1 cells; Lymphoid; Homo sapiens (Human); CVCL_3728
• In Vitro Model: PBMCs cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: BC-2 cells; N.A.; Homo sapiens (Human); CVCL_1856
• In Vitro Model: HUVEC-C cells; N.A.; Homo sapiens (Human); CVCL_2959
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• Experiment for Molecule Alteration: Flow cytometry; Immunoblotting assay; Cytokine/Chemokine analysis; RT-qPCR; Chromatin immunoprecipitation assay
• Experiment for Drug Resistance: Cell activation assay
• Mechanism Description: Pom increased B7-2/CD86 mRNA, protein, and surface expression in EBV-infected cells but this was virtually eliminated in EBV-infected cells made resistant to Pom-induced cytostatic effects. This indicates that Pom initiates the upregulation of these markers by interacting with its target, cereblon. Interestingly, Pom increased the proinflammatory cytokines IP-10 and MIP-1alpha/beta in EBV infected cells, supporting a possible role for the phosphoinositide 3-kinase (PI3K)/AKT pathway in Pom's effects. Idelalisib, an inhibitor of the delta subunit of PI3 Kinase, blocked AKT-Ser phosphorylation and Pom-induced B7-2 surface expression. PU.1 is a downstream target for AKT that is expressed in EBV-infected cells. Pom treatment led to an increase in PU.1 binding to the B7-2 promoter based on ChIP analysis. Thus, our data indicates Pom acts through cereblon leading to degradation of Ikaros and activation of the PI3K/AKT/PU.1 pathway resulting in upregulation of B7-2 mRNA and protein expression. The increased immune recognition in addition to the increases in proinflammatory cytokines upon Pom treatment suggests Pom may be useful in the treatment of EBV-positive lymphomas.

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: DNA-binding protein Ikaros (IKZF1) [1]

• Sensitive Disease: Epstein-barr virus (ebv) infection [ICD-11: XN0R2]
• Sensitive Drug: Pomalidomide
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Daudi cells; Peripheral blood; Homo sapiens (Human); CVCL_0008
• In Vitro Model: Namalwa cells; Lymphoid; Homo sapiens (Human); CVCL_0067
• In Vitro Model: EBV-negative BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: EBV-positive BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: BCBL-1 cells; Peritoneal fluid; Homo sapiens (Human); CVCL_0165
• In Vitro Model: JSC-1 cells; Lymphoid; Homo sapiens (Human); CVCL_3728
• In Vitro Model: PBMCs cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: BC-2 cells; N.A.; Homo sapiens (Human); CVCL_1856
• In Vitro Model: HUVEC-C cells; N.A.; Homo sapiens (Human); CVCL_2959
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• Experiment for Molecule Alteration: Flow cytometry; Immunoblotting assay; Cytokine/Chemokine analysis; RT-qPCR; Chromatin immunoprecipitation assay
• Experiment for Drug Resistance: Cell activation assay
• Mechanism Description: Pom increased B7-2/CD86 mRNA, protein, and surface expression in EBV-infected cells but this was virtually eliminated in EBV-infected cells made resistant to Pom-induced cytostatic effects. This indicates that Pom initiates the upregulation of these markers by interacting with its target, cereblon. Interestingly, Pom increased the proinflammatory cytokines IP-10 and MIP-1alpha/beta in EBV infected cells, supporting a possible role for the phosphoinositide 3-kinase (PI3K)/AKT pathway in Pom's effects. Idelalisib, an inhibitor of the delta subunit of PI3 Kinase, blocked AKT-Ser phosphorylation and Pom-induced B7-2 surface expression. PU.1 is a downstream target for AKT that is expressed in EBV-infected cells. Pom treatment led to an increase in PU.1 binding to the B7-2 promoter based on ChIP analysis. Thus, our data indicates Pom acts through cereblon leading to degradation of Ikaros and activation of the PI3K/AKT/PU.1 pathway resulting in upregulation of B7-2 mRNA and protein expression. The increased immune recognition in addition to the increases in proinflammatory cytokines upon Pom treatment suggests Pom may be useful in the treatment of EBV-positive lymphomas.

Key Molecule: AKT serine/threonine kinase (AKT) [1]

• Sensitive Disease: Epstein-barr virus (ebv) infection [ICD-11: XN0R2]
• Sensitive Drug: Pomalidomide
• Molecule Alteration: Phosphorylation; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Daudi cells; Peripheral blood; Homo sapiens (Human); CVCL_0008
• In Vitro Model: Namalwa cells; Lymphoid; Homo sapiens (Human); CVCL_0067
• In Vitro Model: EBV-negative BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: EBV-positive BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: BCBL-1 cells; Peritoneal fluid; Homo sapiens (Human); CVCL_0165
• In Vitro Model: JSC-1 cells; Lymphoid; Homo sapiens (Human); CVCL_3728
• In Vitro Model: PBMCs cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: BC-2 cells; N.A.; Homo sapiens (Human); CVCL_1856
• In Vitro Model: HUVEC-C cells; N.A.; Homo sapiens (Human); CVCL_2959
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• Experiment for Molecule Alteration: Flow cytometry; Immunoblotting assay; Cytokine/Chemokine analysis; RT-qPCR; Chromatin immunoprecipitation assay
• Experiment for Drug Resistance: Cell activation assay
• Mechanism Description: Pom increased B7-2/CD86 mRNA, protein, and surface expression in EBV-infected cells but this was virtually eliminated in EBV-infected cells made resistant to Pom-induced cytostatic effects. This indicates that Pom initiates the upregulation of these markers by interacting with its target, cereblon. Interestingly, Pom increased the proinflammatory cytokines IP-10 and MIP-1alpha/beta in EBV infected cells, supporting a possible role for the phosphoinositide 3-kinase (PI3K)/AKT pathway in Pom's effects. Idelalisib, an inhibitor of the delta subunit of PI3 Kinase, blocked AKT-Ser phosphorylation and Pom-induced B7-2 surface expression. PU.1 is a downstream target for AKT that is expressed in EBV-infected cells. Pom treatment led to an increase in PU.1 binding to the B7-2 promoter based on ChIP analysis. Thus, our data indicates Pom acts through cereblon leading to degradation of Ikaros and activation of the PI3K/AKT/PU.1 pathway resulting in upregulation of B7-2 mRNA and protein expression. The increased immune recognition in addition to the increases in proinflammatory cytokines upon Pom treatment suggests Pom may be useful in the treatment of EBV-positive lymphomas.

Key Molecule: Transcription factor PU.1 (SPI1) [1]

• Sensitive Disease: Epstein-barr virus (ebv) infection [ICD-11: XN0R2]
• Sensitive Drug: Pomalidomide
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• Cell Pathway Regulation: PI3K/AKT signaling pathway; Activation; hsa04151
• In Vitro Model: Daudi cells; Peripheral blood; Homo sapiens (Human); CVCL_0008
• In Vitro Model: Namalwa cells; Lymphoid; Homo sapiens (Human); CVCL_0067
• In Vitro Model: EBV-negative BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: EBV-positive BL41 cells; Lymphoid; Homo sapiens (Human); N.A.
• In Vitro Model: BCBL-1 cells; Peritoneal fluid; Homo sapiens (Human); CVCL_0165
• In Vitro Model: JSC-1 cells; Lymphoid; Homo sapiens (Human); CVCL_3728
• In Vitro Model: PBMCs cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: BC-2 cells; N.A.; Homo sapiens (Human); CVCL_1856
• In Vitro Model: HUVEC-C cells; N.A.; Homo sapiens (Human); CVCL_2959
• In Vitro Model: U937 cells; Blood; Homo sapiens (Human); CVCL_0007
• Experiment for Molecule Alteration: Flow cytometry; Immunoblotting assay; Cytokine/Chemokine analysis; RT-qPCR; Chromatin immunoprecipitation assay
• Experiment for Drug Resistance: Cell activation assay
• Mechanism Description: Pom increased B7-2/CD86 mRNA, protein, and surface expression in EBV-infected cells but this was virtually eliminated in EBV-infected cells made resistant to Pom-induced cytostatic effects. This indicates that Pom initiates the upregulation of these markers by interacting with its target, cereblon. Interestingly, Pom increased the proinflammatory cytokines IP-10 and MIP-1alpha/beta in EBV infected cells, supporting a possible role for the phosphoinositide 3-kinase (PI3K)/AKT pathway in Pom's effects. Idelalisib, an inhibitor of the delta subunit of PI3 Kinase, blocked AKT-Ser phosphorylation and Pom-induced B7-2 surface expression. PU.1 is a downstream target for AKT that is expressed in EBV-infected cells. Pom treatment led to an increase in PU.1 binding to the B7-2 promoter based on ChIP analysis. Thus, our data indicates Pom acts through cereblon leading to degradation of Ikaros and activation of the PI3K/AKT/PU.1 pathway resulting in upregulation of B7-2 mRNA and protein expression. The increased immune recognition in addition to the increases in proinflammatory cytokines upon Pom treatment suggests Pom may be useful in the treatment of EBV-positive lymphomas.

References

• Ref 1: Mechanism and therapeutic implications of pomalidomide-induced immune surface marker upregulation in EBV-positive lymphomas. Sci Rep. 2023 Jul 18;13(1):11596.