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Review
. 2019 May 23;133(21):2263-2268.
doi: 10.1182/blood-2019-01-852392. Epub 2019 Mar 25.

Genetics and mechanisms of NT5C2-driven chemotherapy resistance in relapsed ALL

Chelsea L Dieck  1 , Adolfo Ferrando  1   2   3   4
Affiliations
Review

Genetics and mechanisms of NT5C2-driven chemotherapy resistance in relapsed ALL

Chelsea L Dieck et al. Blood. .

Abstract

Mutations in the cytosolic 5' nucleotidase II (NT5C2) gene drive resistance to thiopurine chemotherapy in relapsed acute lymphoblastic leukemia (ALL). Mechanistically, NT5C2 mutant proteins have increased nucleotidase activity as a result of altered activating and autoregulatory switch-off mechanisms. Leukemias with NT5C2 mutations are chemoresistant to 6-mercaptopurine yet show impaired proliferation and self-renewal. Direct targeting of NT5C2 or inhibition of compensatory pathways active in NT5C2 mutant cells may antagonize the emergence of NT5C2 mutant clones driving resistance and relapse in ALL.

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Conflict of interest statement

Conflict-of-interest disclosure: The authors declare no competing financial interests.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Purine and thiopurine metabolism. NT5C2 dephosphorylates endogenous and thiopurine-generated 6-hydroxypurine monophosphates before they are exported out of the cell. AICAR, 5-aminoimidazole-4-carboxamide ribonucleotide; dGTP, deoxyguanosine triphosphate; GMPS, guanosine monophosphate synthase; HGPRT, hypoxanthine-guanine phosphoribosyltransferase; IMPDH, inosine monophosphate dehydrogenase; Me6-MP, methyl 6-MP; Me6-TG, methyl 6-thioguanine; MeTIMP, methyl thioinosine monophosphate; NUDT15, Nudix hydrolase 15; PRPP, phosphoribosyl pyrophosphate; TPMT, thiopurine methyltransferase; XO, xanthine oxidase.
Figure 2.
Figure 2.
NT5C2 relapse-associated mutations. (A) NT5C2 relapse-associated mutations in B-cell ALL, T-cell ALL, and acute promyelocytic leukemia (APL). (B) Schematic representation of NT5C2 regulation. NT5C2 dimer protein is depicted with the arm region shown in pink, C terminus in royal blue, N terminus in orange, and helix A in purple. The arm region shown in gray represents a prediction based on modeling. Class I NT5C2 mutants lock the protein in an active helix A configuration. Class II NT5C2 mutants disrupt a switch-off mechanism mediated by the arm and intermonomeric pocket regions. The class III NT5C2 mutant protein lacks the C-terminus stabilizing element, leaving the protein in a more open configuration.
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