Details of Disease

General Information of Disease (ID: DISX02WS)

• Disease Name: Progressive multifocal leukoencephalopathy
• Synonyms: leukoencephalopathy, progressive multifocal; PML; progressive multifocal leukoencephalitis
• Disease Class: 8A45: Secondary white matter disorder
• Definition: Progressive multifocal leukoencephalopathy (PML) is a neurological disorder that damages the myelin that covers and protects nerves in the white matter of the brain. It is caused by the JC virus (JCV). By age 10, most people have been infected with this virus, but itrarelycauses symptoms unless the immune system becomes severely weakened.The disease occurs, rarely, in organ transplant patients; people undergoing chronic corticosteroid or immunosuppressive therapy; and individuals with cancer, such as Hodgkins disease, lymphoma, and sarcoidosis. PML is most common among individuals with acquired immune deficiency syndrome (AIDS).
• Disease Hierarchy:
  DISTC30O: Infectious encephalitis
  DISX02WS: Progressive multifocal leukoencephalopathy
• ICD Code:
  ICD-11: ICD-11: 8A45.02
  ICD-10: ICD-10: A81.2
  Expand ICD-11: '8A45.02
  Expand ICD-10: 'A81.2
• Disease Identifiers:
  MONDO ID: MONDO_0016318
  MESH ID: D007968
  UMLS CUI: C0023524
  MedGen ID: 7327
  Orphanet ID: 217260
  SNOMED CT ID: 22255007

Drug-Interaction Atlas (DIA) of This Disease

This Disease is Treated as An Indication in 1 Approved Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
Mefloquine	DMWT905	Approved	Small molecular drug	[1]

This Disease is Treated as An Indication in 1 Clinical Trial Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
NT-I7	DMISPY7	Phase 1	Recombinant protein	[2]

This Disease is Treated as An Indication in 1 Investigative Drug(s)

Drug Name	Drug ID	Highest Status	Drug Type	REF
JCV-specific TCR a chains-CD3zeta fusion protein	DM5AF7D	Investigative	NA	[3]

Molecular Interaction Atlas (MIA) of This Disease

This Disease Is Related to 10 DTT Molecule(s)

Gene Name	DTT ID	Evidence Level	Mode of Inheritance	REF
PAX5	TTA4REJ	Disputed	Biomarker	[4]
CTDSP1	TTHZAF0	Strong	Biomarker	[5]
GAD1	TTKGEP3	Strong	Biomarker	[6]
KAT6A	TT6O1J0	Strong	Genetic Variation	[7]
MKNK1	TTEZAUX	Strong	Biomarker	[8]
NCOA3	TT124R0	Strong	Biomarker	[9]
RNPEP	TTD74YX	Strong	Genetic Variation	[10]
SENP1	TTW9HY5	Strong	Altered Expression	[11]
TERF1	TT1Y6J2	Strong	Biomarker	[12]
UBA1	TTXHWA7	Strong	Biomarker	[13]

This Disease Is Related to 1 DTP Molecule(s)

Gene Name	DTP ID	Evidence Level	Mode of Inheritance	REF
SLC50A1	DTI9CQU	Strong	Biomarker	[5]

This Disease Is Related to 52 DOT Molecule(s)

Gene Name	DOT ID	Evidence Level	Mode of Inheritance	REF
SENP3	OTFQDOMC	Limited	Biomarker	[14]
SNIP1	OTL3RA91	Limited	Biomarker	[15]
DAXX	OTX6O7PL	moderate	Biomarker	[16]
PRAM1	OTZN3DWD	moderate	Biomarker	[13]
SUMO2	OT1Y5IKN	moderate	Biomarker	[16]
APBB1	OTZPVSSC	Strong	Biomarker	[17]
ARSF	OTC0L12N	Strong	Biomarker	[18]
ATRX	OT77RSQW	Strong	Biomarker	[19]
BLNK	OTSSPF6F	Strong	Biomarker	[4]
CEBPE	OTKZA25M	Strong	Altered Expression	[20]
CTDSPL	OTZJ0CZK	Strong	Altered Expression	[5]
DISC1	OT43AW4H	Strong	Biomarker	[21]
ELK4	OTVSSEOE	Strong	Biomarker	[22]
FYB1	OT6345CH	Strong	Genetic Variation	[23]
GCN1	OTBFVD7Z	Strong	Biomarker	[24]
GINS2	OT974IYI	Strong	Biomarker	[25]
HIRA	OTON40EJ	Strong	Biomarker	[26]
HMBOX1	OTPKTBVI	Strong	Biomarker	[27]
IFI16	OT4SPU0U	Strong	Biomarker	[19]
IGHMBP2	OTAZFPF5	Strong	Biomarker	[28]
LMNB1	OT100T3P	Strong	Biomarker	[9]
MXD4	OTUCXFRO	Strong	Biomarker	[29]
NCKIPSD	OT24UORN	Strong	Altered Expression	[30]
NCOR1	OT04XNOU	Strong	Altered Expression	[31]
NPB	OT0U82T3	Strong	Biomarker	[32]
NRSN1	OT1KKXC8	Strong	Biomarker	[33]
NSMCE2	OTJXLDC9	Strong	Biomarker	[12]
NT5C3A	OT67KZJA	Strong	Biomarker	[34]
ORC5	OTFPW8DE	Strong	Biomarker	[35]
PDIK1L	OTISF4KG	Strong	Biomarker	[36]
POU2AF1	OTOO6WHL	Strong	Altered Expression	[37]
PRPF8	OTU39JZI	Strong	Altered Expression	[38]
PSAP	OTUOEKY7	Strong	Biomarker	[22]
PSMD4	OTH1VZTM	Strong	Biomarker	[18]
PTPRH	OTDUHQGF	Strong	Biomarker	[22]
RAD21	OTQS84ZF	Strong	Biomarker	[39]
SCLT1	OT2ZSSP4	Strong	Biomarker	[22]
SCP2	OTPAFCPQ	Strong	Biomarker	[5]
SCPEP1	OT43LYEZ	Strong	Biomarker	[5]
SMC5	OT91M6N4	Strong	Biomarker	[40]
SP100	OTN8SD5W	Strong	Biomarker	[41]
SPIB	OTO4YKYI	Strong	Altered Expression	[42]
SRSF1	OTF61HOV	Strong	Biomarker	[18]
SUMO1	OTJFD4P5	Strong	Biomarker	[41]
SUMO3	OTTUJQJ1	Strong	Biomarker	[43]
SYCP1	OTWFV4KA	Strong	Biomarker	[5]
SYCP3	OTKOF54H	Strong	Altered Expression	[5]
TAT	OT2CJ91O	Strong	Biomarker	[44]
TCHP	OTVDMHSY	Strong	Biomarker	[45]
TMED2	OTBLO7RW	Strong	Biomarker	[33]
TPPP	OTCFMSUF	Strong	Biomarker	[33]
TRIM69	OTTEGTRD	Strong	Biomarker	[46]

References

• [1] Mefloquine FDA Label
• [2] ClinicalTrials.gov (NCT04781309) NT-I7, a Long-Acting Recombinant IL-7 Molecule, as an Immune Reconstitution Strategy for Lymphopenia in Patients With Progressive Multifocal Leukoencephalopathy. U.S. National Institutes of Health.
• [3] The ChEMBL database in 2017. Nucleic Acids Res. 2017 Jan 4;45(D1):D945-D954.
• [4] B Cell Linker Protein (BLNK) Is a Selective Target of Repression by PAX5-PML Protein in the Differentiation Block That Leads to the Development of Acute Lymphoblastic Leukemia.J Biol Chem. 2016 Feb 26;291(9):4723-31. doi: 10.1074/jbc.M115.637835. Epub 2015 Dec 24.
• [5] SCP phosphatases suppress renal cell carcinoma by stabilizing PML and inhibiting mTOR/HIF signaling.Cancer Res. 2014 Dec 1;74(23):6935-46. doi: 10.1158/0008-5472.CAN-14-1330. Epub 2014 Oct 7.
• [6] JC virus infection of meningeal and choroid plexus cells in patients with progressive multifocal leukoencephalopathy.J Neurovirol. 2019 Aug;25(4):520-524. doi: 10.1007/s13365-019-00753-y. Epub 2019 Apr 25.
• [7] MOZ increases p53 acetylation and premature senescence through its complex formation with PML.Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):3895-900. doi: 10.1073/pnas.1300490110. Epub 2013 Feb 19.
• [8] Translational control of PML contributes to TNF-induced apoptosis of MCF7 breast cancer cells and decreased angiogenesis in HUVECs.Cell Death Differ. 2016 Mar;23(3):469-83. doi: 10.1038/cdd.2015.114. Epub 2015 Sep 18.
• [9] Intrinsically Disordered SRC-3/AIB1 Protein Undergoes Homeostatic Nuclear Extrusion by Nuclear Budding While Ectopic Expression Induces Nucleophagy.Cells. 2019 Oct 19;8(10):1278. doi: 10.3390/cells8101278.
• [10] Telomerase-negative immortalized human cells contain a novel type of promyelocytic leukemia (PML) body.Cancer Res. 1999 Sep 1;59(17):4175-9.
• [11] Modification of nuclear PML protein by SUMO-1 regulates Fas-induced apoptosis in rheumatoid arthritis synovial fibroblasts.Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5073-8. doi: 10.1073/pnas.0608773104. Epub 2007 Mar 14.
• [12] De novo assembly of a PML nuclear subcompartment occurs through multiple pathways and induces telomere elongation.J Cell Sci. 2011 Nov 1;124(Pt 21):3603-18. doi: 10.1242/jcs.084681. Epub 2011 Nov 1.
• [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] SENP3-mediated de-conjugation of SUMO2/3 from promyelocytic leukemia is correlated with accelerated cell proliferation under mild oxidative stress.J Biol Chem. 2010 Apr 23;285(17):12906-15. doi: 10.1074/jbc.M109.071431. Epub 2010 Feb 24.
• [15] Selective activation of NFAT by promyelocytic leukemia protein.Oncogene. 2008 Jun 19;27(27):3821-30. doi: 10.1038/onc.2008.2. Epub 2008 Feb 4.
• [16] Solubility changes of promyelocytic leukemia (PML) and SUMO monomers and dynamics of PML nuclear body proteins in arsenite-treated cells.Toxicol Appl Pharmacol. 2018 Dec 1;360:150-159. doi: 10.1016/j.taap.2018.10.001. Epub 2018 Oct 5.
• [17] Critical role of presenilin-dependent -secretase activity in DNA damage-induced promyelocytic leukemia protein expression and apoptosis.Cell Death Differ. 2013 Apr;20(4):639-48. doi: 10.1038/cdd.2012.162. Epub 2013 Jan 11.
• [18] Early reduction of the splicing factor2/alternative splicing factor: a cellular inhibitor of the JC polyomavirus in natalizumab-treated MS patients long before developing progressive multifocal leukoencephalopathy.J Neurovirol. 2020 Feb;26(1):133-137. doi: 10.1007/s13365-019-00793-4. Epub 2019 Aug 29.
• [19] Role for a Filamentous Nuclear Assembly of IFI16, DNA, and Host Factors in Restriction of Herpesviral Infection.mBio. 2019 Jan 22;10(1):e02621-18. doi: 10.1128/mBio.02621-18.
• [20] PML/RARa blocks the differentiation and promotes the proliferation of acute promyelocytic leukemia through activating MYB expression by transcriptional and epigenetic regulation mechanisms.J Cell Biochem. 2019 Feb;120(2):1210-1220. doi: 10.1002/jcb.27077. Epub 2018 Oct 18.
• [21] Nuclear DISC1 regulates CRE-mediated gene transcription and sleep homeostasis in the fruit fly.Mol Psychiatry. 2008 Dec;13(12):1138-48, 1069. doi: 10.1038/mp.2008.101. Epub 2008 Sep 2.
• [22] Molecular characterization of a JC virus (Sap-1) clone derived from a cerebellar form of progressive multifocal leukoencephalopathy.Acta Neuropathol. 1992;83(2):105-12. doi: 10.1007/BF00308469.
• [23] PRAM-1 is a novel adaptor protein regulated by retinoic acid (RA) and promyelocytic leukemia (PML)-RA receptor alpha in acute promyelocytic leukemia cells.J Biol Chem. 2001 Jun 22;276(25):22375-81. doi: 10.1074/jbc.M011683200. Epub 2001 Apr 11.
• [24] JC virus granule cell neuronopathy is associated with VP1 C terminus mutants.J Gen Virol. 2012 Jan;93(Pt 1):175-183. doi: 10.1099/vir.0.037440-0. Epub 2011 Sep 21.
• [25] Roles of GINS2 in K562 human chronic myelogenous leukemia and NB4 acute promyelocytic leukemia cells.Int J Mol Med. 2013 Jun;31(6):1402-10. doi: 10.3892/ijmm.2013.1339. Epub 2013 Apr 8.
• [26] PML protein organizes heterochromatin domains where it regulates histone H3.3 deposition by ATRX/DAXX.Genome Res. 2017 Jun;27(6):913-921. doi: 10.1101/gr.215830.116. Epub 2017 Mar 24.
• [27] The telomere-associated homeobox-containing protein TAH1/HMBOX1 participates in telomere maintenance in ALT cells.J Cell Sci. 2013 Sep 1;126(Pt 17):3982-9. doi: 10.1242/jcs.128512. Epub 2013 Jun 26.
• [28] Analysis of the transcriptional control region in progressive multifocal leukoencephalopathy.J Neurovirol. 2000 Oct;6(5):398-409. doi: 10.3109/13550280009018304.
• [29] Detection of JC virus DNA in peripheral lymphocytes from patients with and without progressive multifocal leukoencephalopathy.Ann Neurol. 1992 Apr;31(4):454-62. doi: 10.1002/ana.410310426.
• [30] Discovery and characterization of novel trans-spliced products of human polyoma JC virus late transcripts from PML patients.J Cell Physiol. 2018 May;233(5):4137-4155. doi: 10.1002/jcp.26219. Epub 2017 Dec 18.
• [31] The fusion oncoprotein PML-RARalpha induces endoplasmic reticulum (ER)-associated degradation of N-CoR and ER stress.J Biol Chem. 2004 Mar 19;279(12):11814-24. doi: 10.1074/jbc.M312121200. Epub 2003 Dec 29.
• [32] Use of a GFP-PML-expressing cell line as a biosensor for human cytomegalovirus infection.Methods Mol Biol. 2009;515:33-44. doi: 10.1007/978-1-59745-559-6_3.
• [33] Detection of HIV-1 Tat and JCV capsid protein, VP1, in AIDS brain with progressive multifocal leukoencephalopathy.J Neurovirol. 2000 Jun;6(3):221-8. doi: 10.3109/13550280009015824.
• [34] Chimeric immune receptors (CIRs) specific to JC virus for immunotherapy in progressive multifocal leukoencephalopathy (PML).Int Immunol. 2007 Sep;19(9):1083-93. doi: 10.1093/intimm/dxm076. Epub 2007 Jul 28.
• [35] PML-like subnuclear bodies, containing XRCC1, juxtaposed to DNA replication-based single-strand breaks.FASEB J. 2019 Feb;33(2):2301-2313. doi: 10.1096/fj.201801379R. Epub 2018 Sep 27.
• [36] CK2 mediates phosphorylation and ubiquitin-mediated degradation of the PML tumor suppressor.Mol Cell Biochem. 2008 Sep;316(1-2):149-54. doi: 10.1007/s11010-008-9812-7. Epub 2008 Jun 20.
• [37] MiR-126: a novel route for natalizumab action?.Mult Scler. 2014 Sep;20(10):1363-70. doi: 10.1177/1352458514524998. Epub 2014 Mar 5.
• [38] Specific expression of lncRNA RP13-650J16.1 and TCONS_00023979 in prostate cancer.Biosci Rep. 2018 Oct 31;38(5):BSR20171571. doi: 10.1042/BSR20171571. Print 2018 Oct 31.
• [39] Suppression of RAD21 Induces Senescence of MDA-MB-231 Human Breast Cancer Cells Through RB1 Pathway Activation Via c-Myc Downregulation.J Cell Biochem. 2016 Jun;117(6):1359-69. doi: 10.1002/jcb.25426. Epub 2015 Nov 20.
• [40] Telomeric DNA mediates de novo PML body formation.Mol Biol Cell. 2009 Nov;20(22):4804-15. doi: 10.1091/mbc.e09-04-0309. Epub 2009 Sep 30.
• [41] PML nuclear body-residing proteins sequentially associate with HPV genome after infectious nuclear delivery.PLoS Pathog. 2019 Feb 25;15(2):e1007590. doi: 10.1371/journal.ppat.1007590. eCollection 2019 Feb.
• [42] Lymphocyte gene expression and JC virus noncoding control region sequences are linked with the risk of progressive multifocal leukoencephalopathy.J Virol. 2014 May;88(9):5177-83. doi: 10.1128/JVI.03221-13. Epub 2014 Feb 19.
• [43] SUMOylation promotes PML degradation during encephalomyocarditis virus infection.J Virol. 2010 Nov;84(22):11634-45. doi: 10.1128/JVI.01321-10. Epub 2010 Sep 8.
• [44] Multiple roles for Puralpha in cellular and viral regulation.Cell Cycle. 2009 Feb 1;8(3):1-7. doi: 10.4161/cc.8.3.7585. Epub 2009 Feb 10.
• [45] Hepatitis C virus core protein inhibits tumor suppressor protein promyelocytic leukemia function in human hepatoma cells.Cancer Res. 2005 Dec 1;65(23):10830-7. doi: 10.1158/0008-5472.CAN-05-0880.
• [46] Forced expression of RNF36 induces cell apoptosis.Exp Cell Res. 2003 Jul 15;287(2):301-13. doi: 10.1016/s0014-4827(03)00110-1.