Role of 5′-nucleotidase in thiopurine metabolism: Enzyme kinetic profile and association with thio-GMP levels in patients with acute lymphoblastic leukemia during 6-mercaptopurine treatment

Brouwer, C.; Vogels-Mentink, Trude M.; Keizer-Garritsen, Jenneke J.; Trijbels, Frans J.M.; Bökkerink, J.P.M.; Hoogerbrugge, Peter M.; Wering, E. R. Van; Abreu, Ronney A. De

doi:10.1016/j.cccn.2005.05.006

Cited by 18 publications

(11 citation statements)

References 18 publications

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“…This activity controls the intracellular levels of 6-hydroxypurine monophosphate nucleotides via their dephosphorylation to nucleosides, which are subsequently exported out of the cell 14,15 . In addition, NT5C2 metabolizes and inactivates the active metabolites that mediate the cytotoxic activity of 6-MP, a purine analog chemotherapy drug broadly used in the treatment of ALL 16 (Extended Data Fig. 1).…”

mentioning

confidence: 99%

Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia

Tzoneva

Dieck

Oshima

et al. 2018

Nature

104

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Relapsed acute lymphoblastic leukemia (ALL) is associated with chemotherapy resistance and poor prognosis1. Gain-of-function mutations in the 5′-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine (6-MP) and are selectively present in relapsed ALL2,3. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during leukemia initiation, disease progression and relapse remain unknown. Using a conditional inducible leukemia model, we demonstrate that expression of Nt5c2 p.R367Q, a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-MP at the cost of impaired leukemia cell growth and leukemia-initiating cell activity. The loss of fitness phenotype of Nt5c2+/R367Q mutant cells is associated with excess export of purines to the extracellular space and depletion of the intracellular purine nucleotide pool. Consequently, blocking guanosine synthesis via inosine-5′-monophosphate dehydrogenase (IMPDH) inhibition induced increased cytotoxicity against NT5C2-mutant leukemia lymphoblasts. These results identify NT5C2 mutation-associated fitness cost and resistance to chemotherapy as key evolutionary drivers shaping clonal evolution in relapsed ALL and support a role for IMPDH inhibition in the treatment of ALL.

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mentioning

confidence: 99%

Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia

Tzoneva

Dieck

Oshima

et al. 2018

Nature

104

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“…NT5C2 is a ubiquitous enzyme responsible for the final dephosphorylation of 6-hydroxypurine nucleotide monophosphates such as IMP, dIMP, GMP, dGMP and XMP before they can be exported out of the cell 20,21 . In addition, and most notably, NT5C2 can also dephosphorylate and inactivate 6-thioinositol monophosphate and 6-thioguanosine monophosphate which mediate the cytotoxic effects of 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) 22 , two nucleoside analogs commonly used in the treatment of ALL. Mutation analysis of an extended panel of 98 relapse T-ALL (Supplementary Table 1) and 35 relapse B-precursor ALL samples (Supplementary Table 1) identified 22 additional mutations T-ALL and one additional NT5C2 mutation in a B-precursor ALL patient in first relapse (Fig.…”

mentioning

confidence: 99%

“…Given the described role of NT5C2 in the metabolism and inactivation of nucleoside analog drugs 22–24 ; the recurrent finding of the NT5C2 R367Q, NT5C2 R238W and NT5C2 L375F alleles; and the reported association of increased levels of nucleotidase activity with thiopurine resistance and worse clinical outcome 25 , we hypothesized that relapse-associated NT5C2 mutations may represent gain of function alleles with increased enzymatic activity. Detailed structure-function analysis of the NT5C2 K359Q mutation further supported this hypothesis.…”

mentioning

confidence: 99%

Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL

Tzoneva

Pérez-García

Carpenter

et al. 2013

Nat Med

295

317

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Acute lymphoblastic leukemia (ALL) is an aggressive hematological tumor resulting from the malignant transformation of lymphoid progenitors. Despite intensive chemotherapy, 20% of pediatric and over 50% of adult ALL patients fail to achieve a complete remission or relapse after intensified chemotherapy, making disease relapse and resistance to therapy the most significant challenge in the treatment of this disease1,2. Using whole exome sequencing, here we identify mutations in the cytosolic 5'-nucleotidase II gene (NT5C2), which encodes a 5'-nucleotidase enzyme responsible for inactivation of nucleoside analog chemotherapy drugs, in 20/103 (19%) relapse T-ALLs and in 1/35 (3%) relapse B-precursor ALLs analyzed. NT5C2 mutant proteins show increased nucleotidase activity in vitro and conferred resistance to chemotherapy with 6-mercaptopurine and 6-thioguanine when expressed in ALL lymphoblasts. These results support a prominent role for activating mutations in NT5C2 and increased nucleoside analog metabolism in disease progression and chemotherapy resistance in ALL.

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“…In patients with low NT5C activity, treatment with AZA/MP results in the accumulation of thionucleotides and methylthionucleotides [45]. This may represent one explanation for AZA/MP induced myelotoxicity in patients with normal TPMT activity [180].…”

Section: Genetic Factors Affecting Thiopurine Metabolismmentioning

confidence: 98%

“…It is underappreciated that TIMP may also be hydrolyzed by NT5C to form mercaptopurine riboside (MPR), which in turn is a substrate for PNP, generating the MP base [45,46]. Similarly MTIMP can be catabolized to methyl-MPR by NT5C.…”

Section: Future Science Groupmentioning

confidence: 99%

The Pharmacogenetic Basis of Individual Variation in Thiopurine Metabolism

Blaker

Arenas-Hernandez

Sanderson

2012

Personalized Medicine

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Thiopurines are an important class of immunosuppressive therapy, which have been used in clinical practice for over 50 years. Despite this extensive experience many of the pharmacodynamic and pharmacokinetic properties of these drugs remain unknown. As a consequence there is often no clear explanation for the individual variation in response to treatment, both in terms of efficacy or adverse drug reactions. This review, which emphasizes practice in gastroenterology, summarizes the current understanding of thiopurine drug metabolism and highlights the role of nongenetic and genetic factors other than TPMT, which should be a focus for future research. Correlation of polymorphic variations in these genes with clinical outcomes is expected to clarify the basis for interindividual differences in thiopurine metabolism and enable a more personalized approach to therapy.

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Role of 5′-nucleotidase in thiopurine metabolism: Enzyme kinetic profile and association with thio-GMP levels in patients with acute lymphoblastic leukemia during 6-mercaptopurine treatment

Cited by 18 publications

References 18 publications

Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia

Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia

Activating mutations in the NT5C2 nucleotidase gene drive chemotherapy resistance in relapsed ALL

The Pharmacogenetic Basis of Individual Variation in Thiopurine Metabolism

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