Imatinib and chronic myeloid leukemia (Homo sapiens)

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342857CompetitivebindingBone marrowMYCBCRABL1Erythroid differentiationImatinibPVT1Blood1Hematopoietic stem cell (HSC)DifferentiatederythrocyteProliferating CML cellProliferationABCB1ABCG2KITPDGFRAPDGFRBCDKN1BG1/S cell cycle transitionSKP2CSF1R6GADD45AFOXO3NOP2TransportSPRED2LYL1PIM1PIM2MonocyteMonocyte differentiationCSF1RGAB2FLT1


Description

Hematopoietic Stem Cells found in bone marrow can differentiate into Monocytes and Erythrocytes, or in the case of Chronic Myeloid Leukemia (CML), they can continue to proliferate, undifferentiated, in blood. CML is caused by the Philadelphia translocation (Ph), which puts ABL behind BCR. The BRC-ABL fusion is a constitutively on tyrosine kinase that indirectly counteracts erythroid differentiation, thus promoting the continued proliferation underlying CML. Imatinib is a tyrosine kinase inhibitor that binds ABL and in turn promotes healthy erythroid differentiation by counteracting BRC-ABL activity. Imatinib resistance can be conferred by the over-expression of ABC drug transporters and competitive binding kinases.


The pathway diagram above aligns molecules with the cell fates they promote, to help keep track of inhibition-of-inhibition-of-inhibition sequences, for example. The known mechanisms of imatinib resistance are at the bottom, under CML cell fate and are shown interacting with imatinib, which is under the erythrocyte cell fate.

Proteins on this pathway have targeted assays available via the CPTAC Assay Portal

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Bibliography

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  1. Carramusa L, Contino F, Ferro A, Minafra L, Perconti G, Giallongo A, Feo S; ''The PVT-1 oncogene is a Myc protein target that is overexpressed in transformed cells.''; J Cell Physiol, 2007 PubMed Europe PMC Scholia
  2. Colombo T, Farina L, Macino G, Paci P; ''PVT1: a rising star among oncogenic long noncoding RNAs.''; Biomed Res Int, 2015 PubMed Europe PMC Scholia
  3. Amente S, Zhang J, Lavadera ML, Lania L, Avvedimento EV, Majello B; ''Myc and PI3K/AKT signaling cooperatively repress FOXO3a-dependent PUMA and GADD45a gene expression.''; Nucleic Acids Res, 2011 PubMed Europe PMC Scholia
  4. Scheinfeld N; ''A comprehensive review of imatinib mesylate (Gleevec) for dermatological diseases.''; J Drugs Dermatol, 2006 PubMed Europe PMC Scholia
  5. Andreu EJ, Lledó E, Poch E, Ivorra C, Albero MP, Martínez-Climent JA, Montiel-Duarte C, Rifón J, Pérez-Calvo J, Arbona C, Prósper F, Pérez-Roger I; ''BCR-ABL induces the expression of Skp2 through the PI3K pathway to promote p27Kip1 degradation and proliferation of chronic myelogenous leukemia cells.''; Cancer Res, 2005 PubMed Europe PMC Scholia
  6. Daub H, Specht K, Ullrich A; ''Strategies to overcome resistance to targeted protein kinase inhibitors.''; Nat Rev Drug Discov, 2004 PubMed Europe PMC Scholia
  7. Eechoute K, Sparreboom A, Burger H, Franke RM, Schiavon G, Verweij J, Loos WJ, Wiemer EA, Mathijssen RH; ''Drug transporters and imatinib treatment: implications for clinical practice.''; Clin Cancer Res, 2011 PubMed Europe PMC Scholia
  8. Gómez-Casares MT, García-Alegria E, López-Jorge CE, Ferrándiz N, Blanco R, Alvarez S, Vaqué JP, Bretones G, Caraballo JM, Sánchez-Bailón P, Delgado MD, Martín-Perez J, Cigudosa JC, León J; ''MYC antagonizes the differentiation induced by imatinib in chronic myeloid leukemia cells through downregulation of p27(KIP1.).''; Oncogene, 2013 PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
134852view19:40, 27 July 2024EweitzFix truncated text
134851view19:39, 27 July 2024EweitzFlush cache
134850view19:38, 27 July 2024EweitzEconomize layout
134849view19:30, 27 July 2024EweitzStandardize case
134848view19:28, 27 July 2024EweitzFix typo
122579view15:17, 17 April 2022EgonwMade four pathways clickable
117152view09:44, 18 May 2021EweitzModified title
106747view13:23, 17 September 2019MaintBotHMDB identifier normalization
106601view19:44, 10 September 2019KhanspersModified description
105512view06:02, 8 August 2019KhanspersModified description
89384view18:50, 10 September 2016AlexanderPicoOntology Term : 'disease pathway' added !
89383view18:50, 10 September 2016AlexanderPicoOntology Term : 'chronic myeloid leukemia' added !
89382view18:50, 10 September 2016AlexanderPicoOntology Term : 'myeloid leukocyte' added !
89381view18:49, 10 September 2016AlexanderPicoOntology Term : 'chronic myeloid leukemia pathway' added !
89380view18:49, 10 September 2016AlexanderPicoOntology Term : 'erythrocyte' added !
89379view18:48, 10 September 2016AlexanderPicoOntology Term : 'hematopoietic stem cell' added !
85426view23:11, 14 May 2016AlexanderPicoModified title
85425view22:57, 14 May 2016AlexanderPicoModified description
85424view22:53, 14 May 2016AlexanderPicoModified description
85423view22:53, 14 May 2016AlexanderPicoModified description
85422view22:53, 14 May 2016AlexanderPicoModified description
85421view22:51, 14 May 2016AlexanderPicoNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
ABCB1GeneProductENSG00000085563 (Ensembl)
ABCG2GeneProductENSG00000118777 (Ensembl)
ABL1GeneProductENSG00000097007 (Ensembl)
BCRGeneProductENSG00000186716 (Ensembl)
CDKN1BGeneProductENSG00000111276 (Ensembl)
CSF1RGeneProductENSG00000182578 (Ensembl)
Erythroid differentiationPathwayWP2849 (WikiPathways)
FLT1GeneProductENSG00000102755 (Ensembl)
FOXO3GeneProductENSG00000118689 (Ensembl)
G1/S cell cycle transitionPathwayWP45 (WikiPathways)
GAB2GeneProductENSG00000033327 (Ensembl)
GADD45AGeneProductENSG00000116717 (Ensembl)
ImatinibMetaboliteHMDB0014757 (HMDB)
KITGeneProductENSG00000157404 (Ensembl)
LYL1GeneProductENSG00000104903 (Ensembl)
MYCGeneProductENSG00000136997 (Ensembl)
Monocyte differentiationPathwayWP2849 (WikiPathways)
NOP2GeneProductENSG00000111641 (Ensembl)
PDGFRAGeneProductENSG00000134853 (Ensembl)
PDGFRBGeneProductENSG00000113721 (Ensembl)
PIM1GeneProductENSG00000137193 (Ensembl)
PIM2GeneProductENSG00000102096 (Ensembl)
PVT1RnaENSG00000249859 (Ensembl)
ProliferationPathwayWP2849 (WikiPathways)
SKP2GeneProductENSG00000145604 (Ensembl)
SPRED2GeneProductENSG00000198369 (Ensembl)

Annotated Interactions

No annotated interactions

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