Negative feedback–defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL

Li, Benshang; Li, Hui; Bai, Yun; Kirschner-Schwabe, Renate; Yang, Jun J.; Chen, Yao; Lü, Gang; Tzoneva, Gannie; Ma, Xiaotu; Wu, Tongmin; Li, Wenjing; Lu, Haisong; Ding, Lixia; Liang, Huanhuan; Huang, Xiaohang; Yang, Minjun; Jin, Lan; Kang, Hui; Chen, Shuting; Du, Alicia Le; Shen, Shuhong; Ding, Jianping; Chen, Hongzhuan; Chen, Jing; Stackelberg, Arend von; Gu, Long-Jun; Zhang, Jinghui; Ferrando, Adolfo A.; Tang, Jingyan; Wang, Shengyue; Zhou, Bin‐Bing S.

doi:10.1038/nm.3840

Cited by 145 publications

(212 citation statements)

References 42 publications

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“…Once detectable, substantial cytoreduction is never achieved and in each, an inflection point is reached and proliferation accelerates markedly. (Li et al, 2015) This observation is consistent with the assertion that a less proliferative clone escapes therapy and is superseded by more rapidly proliferative clones that predominate at relapse.…”

Section: Discussionsupporting

confidence: 87%

Oligoclonality and new agent evaluation in acute lymphoblastic leukaemia

Gaynon

Sun

2016

Br J Haematol

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New agent development rests on the fundamental assumption that candidate agents or drug combinations that induce objective responses after relapse will prevent relapse, if applied prior to relapse. However, cumulative experience now includes at least 5 examples of interventions with post-relapse objective response rates greater than 50% that failed to improve outcomes when applied prior to relapse. Emerging insights into oligoclonality provide some explanation. In acute lymphoblastic leukaemia, the predominant clones at relapse differ from the predominant clones at presentation. Arguably, the more highly proliferative clones that predominate at relapse differ in drug sensitivity from the less proliferative clones that escape primary therapy. Interventions effective against the predominant clones at relapse may have no effect on the antecedent escapee clones. Response is not sufficient in new agent development. Duration of response has attracted less attention because of variability in post-remission therapy but some patient subsets have such a uniformly dismal outcome that details of post-remission therapy may be irrelevant. Benchmarks are needed. Are recovering blasts members of the same clone or do they represent a new clone? When you eradicate the predominant clones you get a response. When you eradicate all clones, you get a cure.

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Section: Discussionsupporting

confidence: 87%

Oligoclonality and new agent evaluation in acute lymphoblastic leukaemia

Gaynon

Sun

2016

Br J Haematol

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“…We selected recurrently mutated genes that were previously defined as drivers of pediatric ALL 36–38 and relapse-genes 10,39 . Only nonsynonymous single nucleotide variants were used in analysis.…”

Section: Methodsmentioning

confidence: 99%

Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia

Tzoneva

Dieck

Oshima

et al. 2018

Nature

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100

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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“…Mapping of the amino acid alterations on the threedimensional structure of human PRPP synthase isozyme 1 revealed the location of the variations at the allosteric site (Ser102, Asn143, Thr302) or at the dimer interface (Asn113, Gly173, Lys175, Asp182, Ala189, Leu190). The conclusion from this analysis is that the cytotoxic effect of administering compounds such as 6-mercaptopurine and 6-thioguanine may be counteracted by mutations that accelerate the production of PRPP and hence accelerate the de novo synthesis of purine nucleotides, which competes with the cytotoxic compounds (148).…”

Section: Regulation Of Prpp Synthase Activitymentioning

confidence: 99%

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

Hove‐Jensen

Andersen

Kilstrup

et al. 2017

Microbiol Mol Biol Rev

167

187

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SUMMARY Phosphoribosyl diphosphate (PRPP) is an important intermediate in cellular metabolism. PRPP is synthesized by PRPP synthase, as follows: ribose 5-phosphate + ATP → PRPP + AMP. PRPP is ubiquitously found in living organisms and is used in substitution reactions with the formation of glycosidic bonds. PRPP is utilized in the biosynthesis of purine and pyrimidine nucleotides, the amino acids histidine and tryptophan, the cofactors NAD and tetrahydromethanopterin, arabinosyl monophosphodecaprenol, and certain aminoglycoside antibiotics. The participation of PRPP in each of these metabolic pathways is reviewed. Central to the metabolism of PRPP is PRPP synthase, which has been studied from all kingdoms of life by classical mechanistic procedures. The results of these analyses are unified with recent progress in molecular enzymology and the elucidation of the three-dimensional structures of PRPP synthases from eubacteria, archaea, and humans. The structures and mechanisms of catalysis of the five diphosphoryltransferases are compared, as are those of selected enzymes of diphosphoryl transfer, phosphoryl transfer, and nucleotidyl transfer reactions. PRPP is used as a substrate by a large number phosphoribosyltransferases. The protein structures and reaction mechanisms of these phosphoribosyltransferases vary and demonstrate the versatility of PRPP as an intermediate in cellular physiology. PRPP synthases appear to have originated from a phosphoribosyltransferase during evolution, as demonstrated by phylogenetic analysis. PRPP, furthermore, is an effector molecule of purine and pyrimidine nucleotide biosynthesis, either by binding to PurR or PyrR regulatory proteins or as an allosteric activator of carbamoylphosphate synthetase. Genetic analyses have disclosed a number of mutants altered in the PRPP synthase-specifying genes in humans as well as bacterial species.

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Negative feedback–defective PRPS1 mutants drive thiopurine resistance in relapsed childhood ALL

Cited by 145 publications

References 42 publications

Oligoclonality and new agent evaluation in acute lymphoblastic leukaemia

Oligoclonality and new agent evaluation in acute lymphoblastic leukaemia

Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia

Phosphoribosyl Diphosphate (PRPP): Biosynthesis, Enzymology, Utilization, and Metabolic Significance

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