Disease Information

General Information of the Disease (ID: DIS00190)

• Name: Myeloproliferative neoplasm
• ICD: ICD-11: 2A22

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  EADR: Epigenetic Alteration of DNA, RNA or Protein

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

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

Pomalidomide

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Protein cereblon (CRBN) [1]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Nonsense; p.Q100* (c.298C>T)
• Resistant Drug: Pomalidomide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The nonsense p.Q100* (c.298C>T) in gene CRBN cause the resistance of Pomalidomide by unusual activation of pro-survival pathway.

Key Molecule: Protein cereblon (CRBN) [1]

• Resistant Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Missense mutation; p.R283K (c.848G>A)
• Resistant Drug: Pomalidomide
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• Experiment for Molecule Alteration: DNA sequencing assay
• Mechanism Description: The missense mutation p.R283K (c.848G>A) in gene CRBN cause the resistance of Pomalidomide by unusual activation of pro-survival pathway

Clinical Trial Drug(s) 4 drug(s) in total

Ropeginterferon alfa-2b

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [2]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Sensitive Drug: Ropeginterferon alfa-2b
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: HEL cells; Blood; Homo sapiens (Human); CVCL_0001
• In Vitro Model: UKE-1 cells; Peripheral blood; Homo sapiens (Human); CVCL_0104
• Experiment for Drug Resistance: Trypan blue staining assay

BMS-911543

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [3]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Sensitive Drug: BMS-911543
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: [3H] thymidine incorporation assay
• Mechanism Description: The missense mutation p.V617F (c.1849G>T) in gene JAK2 cause the sensitivity of BMS-911543 by aberration of the drug's therapeutic target

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Thrombopoietin receptor (TPOR) [3]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Missense mutation; p.W515L (c.1544G>T)
• Sensitive Drug: BMS-911543
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Western blotting 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

DEBIO-1347

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [4]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Missense mutation; p.Y373C (c.1118A>G)
• Sensitive Drug: DEBIO-1347
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 327 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [4]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Missense mutation; p.F386L (c.1156T>C)
• Sensitive Drug: DEBIO-1347
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 327 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [4]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Missense mutation; p.K650E (c.1948A>G)
• Sensitive Drug: DEBIO-1347
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: 327 cells; N.A.; .; N.A.
• In Vivo Model: Female BALB-nu/nu mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: CCK-8 assay

Gandotinib

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Epigenetic Alteration of DNA, RNA or Protein (EADR)

Key Molecule: Tyrosine-protein kinase JAK2 (JAK3) [5]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Missense mutation; p.V617F (c.1849G>T)
• Sensitive Drug: Gandotinib
• Experimental Note: Identified from the Human Clinical Data

Preclinical Drug(s) 3 drug(s) in total

CHZ868

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Thrombopoietin receptor (TPOR) [6]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Missense mutation; p.W515L (c.1544G>T)
• Sensitive Drug: CHZ868
• 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 blotting 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)

Key Molecule: Thrombopoietin receptor (TPOR) [7]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Missense mutation; p.W515L (c.1544G>T)
• Sensitive Drug: MK2206
• 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

SU5402

Drug Sensitivity Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Fibroblast growth factor receptor 3 (FGFR3) [8]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Missense mutation; p.K650E (c.1948A>G)
• Sensitive Drug: SU5402
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: Blood vessel; .
• Experiment for Molecule Alteration: Mass spectrum assay
• Experiment for Drug Resistance: CellTiter 96 aqueous one solution cell proliferation assay
• Mechanism Description: The missense mutation p.K650E (c.1948A>G) in gene FGFR3 cause the sensitivity of SU5402 by aberration of the drug's therapeutic target

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)

Key Molecule: E3 ubiquitin-protein ligase CBL (CBL) [9]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Missense mutation; p.C384R (c.1150T>C)
• Sensitive Drug: Pyridone 6
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: TF-1 cells; Bone marrow; Homo sapiens (Human); CVCL_0559
• Experiment for Molecule Alteration: Western blotting analysis
• Experiment for Drug Resistance: XTT assay
• Mechanism Description: The missense mutation p.C384R (c.1150T>C) in gene CBL cause the sensitivity of JAK inhibitors by unusual activation of pro-survival pathway

Key Molecule: Thrombopoietin receptor (TPOR) [10]

• Sensitive Disease: Myeloproliferative neoplasm [ICD-11: 2A22.0]
• Molecule Alteration: Missense mutation; p.W515F (c.1544_1545delGGinsTT)
• Sensitive Drug: Pyridone 6
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Bone marrow; .
• In Vivo Model: Balb/C donor mouse xenograft model; Mus musculus
• Experiment for Molecule Alteration: Western blotting 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: Extramedullary myeloma whole genome sequencing reveals novel mutations in Cereblon, proteasome subunit G2 and the glucocorticoid receptor in multi drug resistant disease. Br J Haematol. 2013 Jun;161(5):748-51. doi: 10.1111/bjh.12291. Epub 2013 Mar 11.
• Ref 2: Ropeginterferon alpha-2b targets JAK2V617F-positive polycythemia vera cells in vitro and in vivoBlood Cancer J. 2018 Oct 4;8(10):94. doi: 10.1038/s41408-018-0133-0.
• Ref 3: 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 4: The fibroblast growth factor receptor genetic status as a potential predictor of the sensitivity to CH5183284/Debio 1347, a novel selective FGFR inhibitorMol Cancer Ther. 2014 Nov;13(11):2547-58. doi: 10.1158/1535-7163.MCT-14-0248. Epub 2014 Aug 28.
• Ref 5: A phase 1 study of the Janus kinase 2 (JAK2)(V617F) inhibitor, gandotinib (LY2784544), in patients with primary myelofibrosis, polycythemia vera, and essential thrombocythemiaLeuk Res. 2017 Oct;61:89-95. doi: 10.1016/j.leukres.2017.08.010. Epub 2017 Aug 31.
• Ref 6: 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 7: 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 8: Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric propertiesCancer Cell. 2013 Apr 15;23(4):477-88. doi: 10.1016/j.ccr.2013.02.019.
• Ref 9: CBL linker region and RING finger mutations lead to enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF) signaling via elevated levels of JAK2 and LYNJ Biol Chem. 2013 Jul 5;288(27):19459-70. doi: 10.1074/jbc.M113.475087. Epub 2013 May 21.
• Ref 10: MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasiaPLoS Med. 2006 Jul;3(7):e270. doi: 10.1371/journal.pmed.0030270.