Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZN3DWD)

• DOT Name: PML-RARA-regulated adapter molecule 1 (PRAM1)
• Synonyms: PRAM; PRAM-1
• Gene Name: PRAM1
• Related Disease:
  Chromosomal disorder
  Neoplasm
  Acute leukaemia
  Advanced cancer
  Atrichia with papular lesions
  Essential thrombocythemia
  leukaemia
  Rheumatoid arthritis
  Thrombocytopenia
  Wilms tumor
  Acute myelogenous leukaemia
  Leukemia
  Progressive multifocal leukoencephalopathy
  Myeloid leukaemia
  Primary biliary cholangitis
• UniProt ID: PRAM_HUMAN
• Pfam ID: PF14603
• Sequence:
  MAHHLPAAMESHQDFRSIKAKFQASQPEPSDLPKKPPKPEFGKLKKFSQPELSEHPKKAP
  LPEFGAVSLKPPPPEVTDLPKKPPPPEVTDLPKKPPPPEVTDLPKKPPPPEVTDLPKKPS
  KLELSDLSKKFPQLGATPFPRKPLQPEVGEAPLKASLPEPGAPARKPLQPDELSHPARPP
  SEPKSGAFPRKLWQPEAGEATPRSPQPELSTFPKKPAQPEFNVYPKKPPQPQVGGLPKKS
  VPQPEFSEAAQTPLWKPQSSEPKRDSSAFPKKASQPPLSDFPKKPPQPELGDLTRTSSEP
  EVSVLPKRPRPAEFKALSKKPPQPELGGLPRTSSEPEFNSLPRKLLQPERRGPPRKFSQP
  EPSAVLKRHPQPEFFGDLPRKPPLPSSASESSLPAAVAGFSSRHPLSPGFGAAGTPRWRS
  GGLVHSGGARPGLRPSHPPRRRPLPPASSLGHPPAKPPLPPGPVDMQSFRRPSAASIDLR
  RTRSAAGLHFQDRQPEDIPQVPDEIYELYDDVEPRDDSSPSPKGRDEAPSVQQAARRPPQ
  DPALRKEKDPQPQQLPPMDPKLLKQLRKAEKAEREFRKKFKFEGEIVVHTKMMIDPNAKT
  RRGGGKHLGIRRGEILEVIEFTSNEEMLCRDPKGKYGYVPRTALLPLETEVYDDVDFCDP
  LENQPLPLGR
• Function: May be involved in myeloid differentiation. May be involved in integrin signaling in neutrophils. Binds to PtdIns(4)P.
• Tissue Specificity: Expressed in peripheral blood leukocytes and bone marrow. Expressed in monocytes, and to a lesser extent in granulocytes and lymphocytes. Not expressed in non hematopoietic tissues except in lung.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chromosomal disorder	DISM5BB5	Definitive	Altered Expression	[1]
Neoplasm	DISZKGEW	Definitive	Genetic Variation	[2]
Acute leukaemia	DISDQFDI	Strong	Altered Expression	[3]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[4]
Atrichia with papular lesions	DIS80CUB	Strong	Genetic Variation	[5]
Essential thrombocythemia	DISWWK11	Strong	Biomarker	[6]
leukaemia	DISS7D1V	Strong	Biomarker	[7]
Rheumatoid arthritis	DISTSB4J	Strong	Altered Expression	[8]
Thrombocytopenia	DISU61YW	Strong	Biomarker	[9]
Wilms tumor	DISB6T16	Strong	Altered Expression	[10]
Acute myelogenous leukaemia	DISCSPTN	moderate	Biomarker	[11]
Leukemia	DISNAKFL	moderate	Genetic Variation	[12]
Progressive multifocal leukoencephalopathy	DISX02WS	moderate	Biomarker	[13]
Myeloid leukaemia	DISMN944	Limited	Altered Expression	[14]
Primary biliary cholangitis	DIS43E0O	Limited	Biomarker	[15]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of PML-RARA-regulated adapter molecule 1 (PRAM1).	[16]

8 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of PML-RARA-regulated adapter molecule 1 (PRAM1).	[17]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of PML-RARA-regulated adapter molecule 1 (PRAM1).	[18]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of PML-RARA-regulated adapter molecule 1 (PRAM1).	[19]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of PML-RARA-regulated adapter molecule 1 (PRAM1).	[20]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of PML-RARA-regulated adapter molecule 1 (PRAM1).	[21]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone increases the expression of PML-RARA-regulated adapter molecule 1 (PRAM1).	[22]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of PML-RARA-regulated adapter molecule 1 (PRAM1).	[23]
PMID27336223-Compound-5	DM6E50A	Patented	PMID27336223-Compound-5 increases the expression of PML-RARA-regulated adapter molecule 1 (PRAM1).	[22]

References

• [1] Oncogenic K-ras cooperates with PML-RAR alpha to induce an acute promyelocytic leukemia-like disease.Blood. 2006 Sep 1;108(5):1708-15. doi: 10.1182/blood-2006-04-015040. Epub 2006 May 4.
• [2] Long term curative effects of sequential therapy with all-trans retinoic acid, arsenious oxide and chemotherapy on patients with acute promyelocytic leukemia.Hematology. 2012 Nov;17(6):311-6. doi: 10.1179/102453312X13451850327262.
• [3] Altered myeloid development and acute leukemia in transgenic mice expressing PML-RAR alpha under control of cathepsin G regulatory sequences.Blood. 1997 Jan 15;89(2):376-87.
• [4] Association of PML-RAR alpha fusion mRNA type with pretreatment hematologic characteristics but not treatment outcome in acute promyelocytic leukemia: an intergroup molecular study.Blood. 1997 Aug 15;90(4):1656-63.
• [5] Variations on a theme: the alternate translocations in APL.Leukemia. 2002 Oct;16(10):1927-32. doi: 10.1038/sj.leu.2402720.
• [6] Acute promyelocytic leukemia developing in untreated essential thrombocythemia.Am J Hematol. 2002 Oct;71(2):114-6. doi: 10.1002/ajh.10195.
• [7] DNA methylation in ATRA-treated leukemia cell lines lacking a PML-RAR chromosome translocation.Anticancer Res. 2012 Nov;32(11):4715-22.
• [8] Molecular signature of retinoic acid treatment in acute promyelocytic leukemia.Oncogene. 2005 May 5;24(20):3358-68. doi: 10.1038/sj.onc.1208498.
• [9] Acute promyelocytic leukemia relapsing into FAB-M2 acute myeloid leukemia with trisomy 8.Cancer Genet Cytogenet. 2000 Feb;117(1):82-3. doi: 10.1016/s0165-4608(99)00132-6.
• [10] Clinical significance of minimal residual disease in childhood acute myeloid leukemia.Int J Hematol. 2004 Apr;79(3):243-9. doi: 10.1532/ijh97.03113.
• [11] KIT and FLT3 receptor tyrosine kinase mutations in acute myeloid leukemia with favorable cytogenetics: two novel mutations and selective occurrence in leukemia subtypes and age groups.Exp Mol Pathol. 2008 Dec;85(3):227-31. doi: 10.1016/j.yexmp.2008.09.004. Epub 2008 Oct 11.
• [12] Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile.Blood. 2013 Aug 15;122(7):1293-304. doi: 10.1182/blood-2013-05-501072. Epub 2013 Jul 8.
• [13] UBE1L represses PML/RAR{alpha} by targeting the PML domain for ISG15ylation.Mol Cancer Ther. 2008 Apr;7(4):905-14. doi: 10.1158/1535-7163.MCT-07-0515.
• [14] A case of acute eosinophilic granulocytic leukemia with PML-RAR alpha fusion gene expression and response to all-trans retinoic acid.Leukemia. 1997 Apr;11(4):609-11. doi: 10.1038/sj.leu.2400600.
• [15] The t(15;17) translocation alters a nuclear body in a retinoic acid-reversible fashion.EMBO J. 1994 Mar 1;13(5):1073-83. doi: 10.1002/j.1460-2075.1994.tb06356.x.
• [16] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [17] Pharmacogenomic analysis of acute promyelocytic leukemia cells highlights CYP26 cytochrome metabolism in differential all-trans retinoic acid sensitivity. Blood. 2007 May 15;109(10):4450-60.
• [18] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [19] PRAM-1 potentiates arsenic trioxide-induced JNK activation. J Biol Chem. 2005 Mar 11;280(10):9043-8. doi: 10.1074/jbc.M413564200. Epub 2005 Jan 6.
• [20] Oxidative stress modulates theophylline effects on steroid responsiveness. Biochem Biophys Res Commun. 2008 Dec 19;377(3):797-802.
• [21] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [22] PPARgamma controls CD1d expression by turning on retinoic acid synthesis in developing human dendritic cells. J Exp Med. 2006 Oct 2;203(10):2351-62.
• [23] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.