Molecule Information

General Information of the Molecule (ID: Mol01866)

• Name: Diphthamide biosynthesis 1 (DPH1) ,Homo sapiens
• Synonyms: DPH1; DPH2L; DPH2L1; OVCA1
• Molecule Type: Protein
• Gene Name: DPH1
• Gene ID: 1801
• Location: chr17:2,030,137-2,043,898[+]
• Sequence:
  MRRQVMAALVVSGAAEQGGRDGPGRGRAPRGRVANQIPPEILKNPQLQAAIRVLPSNYNF
  EIPKTIWRIQQAQAKKVALQMPEGLLLFACTIVDILERFTEAEVMVMGDVTYGACCVDDF
  TARALGADFLVHYGHSCLIPMDTSAQDFRVLYVFVDIRIDTTHLLDSLRLTFPPATALAL
  VSTIQFVSTLQAAAQELKAEYRVSVPQCKPLSPGEILGCTSPRLSKEVEAVVYLGDGRFH
  LESVMIANPNVPAYRYDPYSKVLSREHYDHQRMQAARQEAIATARSAKSWGLILGTLGRQ
  GSPKILEHLESRLRALGLSFVRLLLSEIFPSKLSLLPEVDVWVQVACPRLSIDWGTAFPK
  PLLTPYEAAVALRDISWQQPYPMDFYAGSSLGPWTVNHGQDRRPHAPGRPARGKVQEGSA
  RPPSAVACEDCSCRDEKVAPLAP
• Function: Required for the first step in the synthesis of diphthamide, a post-translational modification of histidine which occurs in translation elongation factor 2 (EEF2). When overexpressed, suppresses colony formation ability and growth rate of ovarian cancer cells. Acts also as a tumor suppressor in lung and breast cancers (By similarity). Plays a role in embryonic growth, organogenesis and postnatal survival (By similarity).
• Uniprot ID: DPH1_HUMAN
• Ensembl ID: ENSG00000108963
• HGNC ID: HGNC:3003

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

Type(s) of Resistant Mechanism of This Molecule

  EADR: Epigenetic Alteration of DNA, RNA or Protein

Drug Resistance Data Categorized by Drug

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

Tagraxofusp

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Disease Class: Blastic plasmacytoid dendritic cell neoplasm [1]

• Resistant Disease: Blastic plasmacytoid dendritic cell neoplasm [ICD-11: 2A60.5]
• Resistant Drug: Tagraxofusp
• Molecule Alteration: Expression; Down-regulation
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Jurkat cells; Pleural effusion; Homo sapiens (Human); CVCL_0065
• In Vitro Model: SAOS-2 cells; Bone marrow; Homo sapiens (Human); CVCL_0548
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vitro Model: MV4-11 cells; Peripheral blood; Homo sapiens (Human); CVCL_0064
• In Vivo Model: NSG mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: Loss of DPH1 is sufficient to confer relative tagraxofusp resistance in AML cells. CpGs further upstream, between -300 and -80 bases from the transcription start site (TSS), showed no significant change in methylation, suggesting that increased DPH1-promoter methylation associated with tagraxofusp resistance may confer a specific advantage. Given this finding, we hypothesized that azacitidine, a DNA methyltransferase inhibitor or DNA hypomethylating agent (HMA) might reverse resistance-associated DPH1 hypermethylation and restore DPH1 expression.

References

• Ref 1: DNA methyltransferase inhibition overcomes diphthamide pathway deficiencies underlying CD123-targeted treatment resistance .J Clin Invest. 2019 Nov 1;129(11):5005-5019. doi: 10.1172/JCI128571. 10.1172/JCI128571