Annotation Detail

Information
Associated Genes
PRPS1
Associated Variants
PRPS1 S103I
PRPS1 S103I
Associated Disease
childhood B-cell acute lymphoblastic leukemia
Source Database
CIViC Evidence
Description
Lentiviral-mediated overexpression of PRPS1 S103T in Reh cells resulted in significant resistance against mercaptopurine (6-MP) and thioguanine (6-TG) as indicated by IC50 increases and reduced apoptosis compared to multiple controls (empty vector and overexpression of wildtype or known reduced-function PRPS1 mutants). 6-MP cytotoxicity results were confirmed using Jurkat cells. After 6-MP exposure, mass spectrometry revealed S103T cells possessed reduced concentrations of intracellular 6-MP metabolites (TIMP, TGMP, etc.) versus controls. S103T cells produce increased intracellular concentrations of hypoxanthine and IMP. Also, after 6-MP exposure, S103T cells display reduced levels of DNA damage response and apoptosis protein markers. S103T results in the activation of the de novo purine synthesis pathway by reducing feedback inhibition, allowing the cell to continue to create nucleotides even when concentrations are elevated. This overactivation creates increased hypoxanthine levels, which likely competitively inhibit thiopurine conversion. The enhanced production of hypoxanthine likely leads to reduced conversion of thiopurines to their active form due to competitive inhibition.
Variant Origin
somatic
Variant Origin
Somatic
Evidence URL
https://civic.genome.wustl.edu/links/evidence_items/7907
Gene URL
https://civic.genome.wustl.edu/links/genes/4566
Variant URL
https://civic.genome.wustl.edu/links/variants/2927
Rating
5
Evidence Type
Predictive
Disease
Childhood B-cell Acute Lymphoblastic Leukemia
Evidence Direction
Supports
Drug
Mercaptopurine,Thioguanine
Evidence Level
D
Clinical Significance
Resistance
Pubmed
25962120
Drugs
Drug NameSensitivitySupported
MercaptopurineResitance or Non-Reponsetrue
ThioguanineResitance or Non-Reponsetrue