Molecule Information

General Information of the Molecule (ID: Mol04343)

• Name: Transcription factor PU.1 (SPI1) ,Homo sapiens
• Synonyms: 31 kDa-transforming protein
• Molecule Type: Protein
• Gene Name: SPI1
• Gene ID: 6688
• Sequence:
  MLQACKMEGFPLVPPPSEDLVPYDTDLYQRQTHEYYPYLSSDGESHSDHYWDFHPHHVHS
  EFESFAENNFTELQSVQPPQLQQLYRHMELEQMHVLDTPMVPPHPSLGHQVSYLPRMCL
  Q YPSLSPAQPSSDEEEGERQSPPLEVSDGEADGLEPGPGLLPGETGSKKKIRLYQFLLD
  LL RSGDMKDSIWWVDKDKGTFQFSSKHKEALAHRWGIQKGNRKKMTYQKMARALRNYGK
  TGE VKKVKKKLTYQFSGEVLGRGGLAERRHPPH
• Function: Pioneer transcription factor, which controls hematopoieticcell fate by decompacting stem cell heterochromatin and allowing othertranscription factors to enter otherwise inaccessible genomic sites.Once in open chromatin, can directly control gene expression by bindinggenetic regulatory elements and can also more broadly influencetranscription by recruiting transcription factors, such as interferonregulatory factors , to otherwise inaccessible genomic regions. Transcriptionally activates genesimportant for myeloid and lymphoid lineages, such as CSF1R . Transcriptional activation from certain promoters,possibly containing low affinity binding sites, is achievedcooperatively with other transcription factors. FCER1A transactivationis achieved in cooperation with GATA1 . May beparticularly important for the pro- to pre-B cell transition. Binds onto the purine-rich DNAcore sequence 5'-GAGGAA-3', also known as the PU-box .In vitro can bind RNA and interfere with pre-mRNA splicing . {ECO:0000250|UniProtKB:P17433,ECO:0000250|UniProtKB:Q6BDS1, ECO:0000269|PubMed:23658224,ECO:0000269|PubMed:33951726}.
• Uniprot ID: SPI1_HUMAN
• Ensembl ID: ENSG0000006633613
• HGNC ID: HGNC:11241

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

Type(s) of Resistant Mechanism of This Molecule

  ADTT: Aberration of the Drug's Therapeutic Target

Drug Resistance Data Categorized by Drug

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

Pomalidomide

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Disease Class: Epstein-barr virus (ebv) infection [ICD-11: XN0R2] [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.