Molecule Information

General Information of the Molecule (ID: Mol01847)

• Name: Thrombopoietin receptor (TPOR) ,Homo sapiens
• Synonyms: Thrombopoietin receptor; TPO-R; Myeloproliferative leukemia protein; Proto-oncogene c-Mpl; CD antigen CD110; MPL
• Molecule Type: Protein
• Gene Name: TPOR
• Gene ID: 4352
• Location: chr1:43,337,818-43,354,466[+]
• Sequence:
  MPSWALFMVTSCLLLAPQNLAQVSSQDVSLLASDSEPLKCFSRTFEDLTCFWDEEEAAPS
  GTYQLLYAYPREKPRACPLSSQSMPHFGTRYVCQFPDQEEVRLFFPLHLWVKNVFLNQTR
  TQRVLFVDSVGLPAPPSIIKAMGGSQPGELQISWEEPAPEISDFLRYELRYGPRDPKNST
  GPTVIQLIATETCCPALQRPHSASALDQSPCAQPTMPWQDGPKQTSPSREASALTAEGGS
  CLISGLQPGNSYWLQLRSEPDGISLGGSWGSWSLPVTVDLPGDAVALGLQCFTLDLKNVT
  CQWQQQDHASSQGFFYHSRARCCPRDRYPIWENCEEEEKTNPGLQTPQFSRCHFKSRNDS
  IIHILVEVTTAPGTVHSYLGSPFWIHQAVRLPTPNLHWREISSGHLELEWQHPSSWAAQE
  TCYQLRYTGEGHQDWKVLEPPLGARGGTLELRPRSRYRLQLRARLNGPTYQGPWSSWSDP
  TRVETATETAWISLVTALHLVLGLSAVLGLLLLRWQFPAHYRRLRHALWPSLPDLHRVLG
  QYLRDTAALSPPKATVSDTCEEVEPSLLEILPKSSERTPLPLCSSQAQMDYRRLQPSCLG
  TMPLSVCPPMAESGSCCTTHIANHSYLPLSYWQQP
• 3D-structure: PDB ID: 8G04; Classification: Cytokine; Method: Electron microscopy; Resolution: 3.40 Å
• Function: Receptor for thrombopoietin that acts as a primary regulator of megakaryopoiesis and platelet production. May represent a regulatory molecule specific for TPO-R-dependent immune responses.
• Uniprot ID: TPOR_HUMAN
• Ensembl ID: ENSG00000117400
• HGNC ID: HGNC:7217

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

Type(s) of Resistant Mechanism of This Molecule

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Clinical Trial Drug(s) 2 drug(s) in total

BMS-911543

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Myeloproliferative neoplasm [ICD-11: 2A22.0] [1]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: BMS-911543
• Molecule Alteration: Missense mutation; p.W515L (c.1544G>T)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: [3H] thymidine incorporation assay
• Mechanism Description: The missense mutation p.W515L (c.1544G>T) in gene MPL cause the sensitivity of BMS-911543 by unusual activation of pro-survival pathway

Disease Class: Hematologic Cancer [ICD-11: MG24.Y] [1]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: BMS-911543
• Molecule Alteration: Missense mutation; p.W515L (c.1544G>T)
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: [3H] thymidine incorporation assay
• Mechanism Description: The missense mutation p.W515L (c.1544G>T) in gene MPL cause the sensitivity of BMS-911543 by unusual activation of pro-survival pathway

NS-018

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hematologic Cancer [ICD-11: MG24.Y] [2]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: NS-018
• Molecule Alteration: Missense mutation; p.W515L (c.1544G>T)
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: Sf9 cells; Ovary; Homo sapiens (Human); CVCL_0549
• Experiment for Molecule Alteration: Colony formation assay
• Experiment for Drug Resistance: MTT assay
• Mechanism Description: The missense mutation p.W515L (c.1544G>T) in gene MPL cause the sensitivity of NS-018 by unusual activation of pro-survival pathway

Preclinical Drug(s) 4 drug(s) in total

BEZ235/Ruxolitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: BEZ235/Ruxolitinib
• Molecule Alteration: Missense mutation; p.W515L (c.1544G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: JAK2 mutant Ba/F3 tumour mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony assay

CHZ868

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Hematologic Cancer [ICD-11: MG24.Y] [4]

• Sensitive Disease: Hematologic Cancer [ICD-11: MG24.Y]
• Sensitive Drug: CHZ868
• Molecule Alteration: Missense mutation; p.W515L (c.1544G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: W515L cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vivo Model: CD45.2 Jak2V617F mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability luminescent assay

Disease Class: Myeloproliferative neoplasm [ICD-11: 2A22.0] [4]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: CHZ868
• Molecule Alteration: Missense mutation; p.W515L (c.1544G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vitro Model: W515L cells; Blood; Homo sapiens (Human); N.A.
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vivo Model: CD45.2 Jak2V617F mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: Cell viability luminescent assay

MK2206

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Myeloproliferative neoplasm [ICD-11: 2A22.0] [5]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: MK2206
• Molecule Alteration: Missense mutation; p.W515L (c.1544G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: SET2 cells; Peripheral blood; Homo sapiens (Human); CVCL_2187
• In Vivo Model: Balb/c donor mouse xenograft model; Mus musculus
• Experiment for Drug Resistance: Trypan blue staining assay
• Mechanism Description: The missense mutation p.W515L (c.1544G>T) in gene MPL cause the sensitivity of MK2206 by unusual activation of pro-survival pathway

Pictilisib/Ruxolitinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Solid tumour/cancer [ICD-11: 2A00-2F9Z] [3]

• Sensitive Disease: Solid tumour/cancer [ICD-11: 2A00-2F9Z]
• Sensitive Drug: Pictilisib/Ruxolitinib
• Molecule Alteration: Missense mutation; p.W515L (c.1544G>T)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Ba/F3 cells; Colon; Homo sapiens (Human); CVCL_0161
• In Vivo Model: JAK2 mutant Ba/F3 tumour mouse model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: CellTiter-Glo assay; Colony assay

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

Pyridone 6

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Disease Class: Myeloproliferative neoplasm [ICD-11: 2A22.0] [6]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Sensitive Drug: Pyridone 6
• Molecule Alteration: Missense mutation; p.W515F (c.1544_1545delGGinsTT)
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; N.A.
• In Vivo Model: Balb/C donor mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blot analysis
• Experiment for Drug Resistance: In vitro colony-forming assay
• Mechanism Description: The missense mutation p.W515F (c.1544_1545delGGinsTT) in gene MPL cause the sensitivity of JAK inhibitors by unusual activation of pro-survival pathway

References

• Ref 1: Characterization of BMS-911543, a functionally selective small-molecule inhibitor of JAK2Leukemia. 2012 Feb;26(2):280-8. doi: 10.1038/leu.2011.292. Epub 2011 Oct 21.
• Ref 2: Efficacy of NS-018, a potent and selective JAK2/Src inhibitor, in primary cells and mouse models of myeloproliferative neoplasmsBlood Cancer J. 2011 Jul;1(7):e29. doi: 10.1038/bcj.2011.29. Epub 2011 Jul 22.
• Ref 3: Combination treatment for myeloproliferative neoplasms using JAK and pan-class I PI3K inhibitorsJ Cell Mol Med. 2013 Nov;17(11):1397-409. doi: 10.1111/jcmm.12156. Epub 2013 Nov 19.
• Ref 4: CHZ868, a Type II JAK2 Inhibitor, Reverses Type I JAK Inhibitor Persistence and Demonstrates Efficacy in Myeloproliferative NeoplasmsCancer Cell. 2015 Jul 13;28(1):15-28. doi: 10.1016/j.ccell.2015.06.006.
• Ref 5: AKT is a therapeutic target in myeloproliferative neoplasmsLeukemia. 2013 Sep;27(9):1882-90. doi: 10.1038/leu.2013.167. Epub 2013 Jun 10.
• Ref 6: MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasiaPLoS Med. 2006 Jul;3(7):e270. doi: 10.1371/journal.pmed.0030270.