Imatinib and chronic myeloid leukemia (WP3640)

Homo sapiens

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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 [https://assays.cancer.gov/available_assays?wp_id=WP3640 CPTAC Assay Portal]

Authors

Alex Pico , Kristina Hanspers , Eric Weitz , and Egon Willighagen

Activity

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Cited In

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Organisms

Homo sapiens

Communities

CPTAC

Annotations

Cell Type Ontology

erythrocyte myeloid leukocyte hematopoietic stem cell

Pathway Ontology

disease pathway chronic myeloid leukemia pathway

Disease Ontology

chronic myeloid leukemia

Participants
Query Drugst.One

Label Type Compact URI Comment
Imatinib Metabolite hmdb:HMDB0014757
BCR GeneProduct ensembl:ENSG00000186716
ABL1 GeneProduct ensembl:ENSG00000097007
MYC GeneProduct ensembl:ENSG00000136997
ABCB1 GeneProduct ensembl:ENSG00000085563
ABCG2 GeneProduct ensembl:ENSG00000118777
KIT GeneProduct ensembl:ENSG00000157404
PDGFRA GeneProduct ensembl:ENSG00000134853
PDGFRB GeneProduct ensembl:ENSG00000113721
CDKN1B GeneProduct ensembl:ENSG00000111276
SKP2 GeneProduct ensembl:ENSG00000145604
CSF1R GeneProduct ensembl:ENSG00000182578
GADD45A GeneProduct ensembl:ENSG00000116717
FOXO3 GeneProduct ensembl:ENSG00000118689
NOP2 GeneProduct ensembl:ENSG00000111641
SPRED2 GeneProduct ensembl:ENSG00000198369
LYL1 GeneProduct ensembl:ENSG00000104903
PIM1 GeneProduct ensembl:ENSG00000137193
PIM2 GeneProduct ensembl:ENSG00000102096
CSF1R GeneProduct ensembl:ENSG00000182578
GAB2 GeneProduct ensembl:ENSG00000033327
FLT1 GeneProduct ensembl:ENSG00000102755

References

  1. Strategies to overcome resistance to targeted protein kinase inhibitors. Daub H, Specht K, Ullrich A. Nat Rev Drug Discov. 2004 Dec;3(12):1001–10. PubMed Europe PMC Scholia
  2. BCR-ABL induces the expression of Skp2 through the PI3K pathway to promote p27Kip1 degradation and proliferation of chronic myelogenous leukemia cells. Andreu EJ, Lledó E, Poch E, Ivorra C, Albero MP, Martínez-Climent JA, et al. Cancer Res. 2005 Apr 15;65(8):3264–72. PubMed Europe PMC Scholia
  3. A comprehensive review of imatinib mesylate (Gleevec) for dermatological diseases. Scheinfeld N. J Drugs Dermatol. 2006 Feb;5(2):117–22. PubMed Europe PMC Scholia
  4. The PVT-1 oncogene is a Myc protein target that is overexpressed in transformed cells. Carramusa L, Contino F, Ferro A, Minafra L, Perconti G, Giallongo A, et al. J Cell Physiol. 2007 Nov;213(2):511–8. PubMed Europe PMC Scholia
  5. Drug transporters and imatinib treatment: implications for clinical practice. Eechoute K, Sparreboom A, Burger H, Franke RM, Schiavon G, Verweij J, et al. Clin Cancer Res. 2011 Feb 1;17(3):406–15. PubMed Europe PMC Scholia
  6. Myc and PI3K/AKT signaling cooperatively repress FOXO3a-dependent PUMA and GADD45a gene expression. Amente S, Zhang J, Lavadera ML, Lania L, Avvedimento EV, Majello B. Nucleic Acids Res. 2011 Dec;39(22):9498–507. PubMed Europe PMC Scholia
  7. MYC antagonizes the differentiation induced by imatinib in chronic myeloid leukemia cells through downregulation of p27(KIP1.). Gómez-Casares MT, García-Alegria E, López-Jorge CE, Ferrándiz N, Blanco R, Alvarez S, et al. Oncogene. 2013 Apr 25;32(17):2239–46. PubMed Europe PMC Scholia
  8. PVT1: a rising star among oncogenic long noncoding RNAs. Colombo T, Farina L, Macino G, Paci P. Biomed Res Int. 2015;2015:304208. PubMed Europe PMC Scholia