Abstract:
:Relapse is the leading cause of mortality in children with acute lymphoblastic leukemia (ALL). Among chemotherapeutics, thiopurines are key drugs in ALL combination therapy. Using whole-exome sequencing, we identified relapse-specific mutations in the phosphoribosyl pyrophosphate synthetase 1 gene (PRPS1), which encodes a rate-limiting purine biosynthesis enzyme, in 24/358 (6.7%) relapsed childhood B cell ALL (B-ALL) cases. All individuals who harbored PRPS1 mutations relapsed early during treatment, and mutated ALL clones expanded exponentially before clinical relapse. Our functional analyses of PRPS1 mutants uncovered a new chemotherapy-resistance mechanism involving reduced feedback inhibition of de novo purine biosynthesis and competitive inhibition of thiopurine activation. Notably, the de novo purine synthesis inhibitor lometrexol effectively abrogated PRPS1 mutant-driven drug resistance. These results highlight the importance of constitutive activation of the de novo purine synthesis pathway in thiopurine resistance, and they offer therapeutic strategies for the treatment of relapsed and thiopurine-resistant ALL.
journal_name
Nat Medjournal_title
Nature medicineauthors
Li B,Li H,Bai Y,Kirschner-Schwabe R,Yang JJ,Chen Y,Lu G,Tzoneva G,Ma X,Wu T,Li W,Lu H,Ding L,Liang H,Huang X,Yang M,Jin L,Kang H,Chen S,Du A,Shen S,Ding J,Chen H,Chen J,von Stackelberg A,Gu L,Zhang J,doi
10.1038/nm.3840subject
Has Abstractpub_date
2015-06-01 00:00:00pages
563-71issue
6eissn
1078-8956issn
1546-170Xpii
nm.3840journal_volume
21pub_type
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