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

Dieck, Chelsea L.; Ferrando, Adolfo A.

doi:10.1182/blood-2019-01-852392

Cited by 40 publications

(42 citation statements)

References 50 publications

(79 reference statements)

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“…6-mercaptopurine (6-MP), a purine base analog commonly used in the treatment of ALL, is incorporated in salvage pathway of purine biosynthesis and induces antitumor effects via inhibition of de novo purine biosynthesis and by inducing apoptosis upon incorporation into DNA (De Abreu 1994). The cytosolic 5 ′ -Nucleotidase II (NT5C2), an enzyme responsible for the intracellular 5 ′ -dephosphorylation of the purine biosynthesis precursors inosine monophosphate (IMP), guanosine monophosphate (GMP), and xanthine monophosphate (XMP), can antagonize the activity of 6-MP by facilitating the dephosphorylation and cellular export of the thiopurine-derived metabolites thio-IMP, thio-XMP, and thio-GMP (Dieck and Ferrando 2019). Notably, somatic activating mutations in NT5C2 are present in 3%-10% of relapsed B-ALL and 20% of relapsed T-ALL cases (Meyer et al 2013;Tzoneva et al 2013;Oshima et al 2016) and can also be found in acute promyelocytic leukemia (APL) relapse samples from patients who have been treated with 6-MP (Lehmann-Che et al 2018).…”

Section: Targeting Nucleotide Biosynthesis and Degradation Pathwaysmentioning

confidence: 99%

Metabolic dependencies and vulnerabilities in leukemia

Rashkovan

Ferrando

2019

Genes Dev.

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Leukemia cell proliferation requires up-regulation and rewiring of metabolic pathways to feed anabolic cell growth. Oncogenic drivers directly and indirectly regulate metabolic pathways, and aberrant metabolism is central not only for leukemia proliferation and survival, but also mediates oncogene addiction with significant implications for the development of targeted therapies. This review explores leukemia metabolic circuitries feeding anabolism, redox potential, and energy required for tumor propagation with an emphasis on emerging therapeutic opportunities.

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Section: Targeting Nucleotide Biosynthesis and Degradation Pathwaysmentioning

confidence: 99%

Metabolic dependencies and vulnerabilities in leukemia

Rashkovan

Ferrando

2019

Genes Dev.

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“…The type III mutations (Q523X) generate a truncated protein due to the loss of the C-terminal tail, impeding a switch toward an inactive protein state [65]. Collectively, these data identify three activating mechanisms by which NT5C2 mutations increase nucleotidase activity, and pave the way for the development of NT5C2 inhibitors to prevent and reverse purine analogue resistance in T-ALL [66].…”

Section: Mechanisms Of Resistance To Standard Chemotherapymentioning

confidence: 99%

Strategies to Overcome Resistance Mechanisms in T-Cell Acute Lymphoblastic Leukemia

Follini

Marchesini

Roti

2019

IJMS

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Chemoresistance is a major cause of recurrence and death from T-cell acute lymphoblastic leukemia (T-ALL), both in adult and pediatric patients. In the majority of cases, drug-resistant disease is treated by selecting a combination of other drugs, without understanding the molecular mechanisms by which malignant cells escape chemotherapeutic treatments, even though a more detailed genomic characterization and the identification of actionable disease targets may enable informed decision of new agents to improve patient outcomes. In this work, we describe pathways of resistance to common chemotherapeutic agents including glucocorticoids and review the resistance mechanisms to targeted therapy such as IL7R, PI3K-AKT-mTOR, NOTCH1, BRD4/MYC, Cyclin D3: CDK4/CDK6, BCL2 inhibitors, and selective inhibitors of nuclear export (SINE). Finally, to overcome the limitations of the current trial-and-error method, we summarize the experiences of anti-cancer drug sensitivity resistance profiling (DSRP) approaches as a rapid and relevant strategy to infer drug activity and provide functional information to assist clinical decision one patient at a time.

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“…Incorporation of genetic biomarkers of drugs may lead to better assessment of their efficacy, as demonstrated by previous clinical trials of PARP inhibitors 49 . Importantly, for nucleoside-based anticancer drugs that are structurally similar to antiviral drugs, numerous clinical studies have shown that SNPs and expression status of their relevant transporters and metabolizing enzymes dictated clinical outcome 50–54 . Therefore, the transportation, activating and detoxifying mechanisms uncovered in this screen may point to clinical biomarkers of COVID-19 drugs.…”

Section: Discussionmentioning

confidence: 99%

Genetic determinants of COVID-19 drug efficacy revealed by genome-wide CRISPR screens

Wei

Yang

et al. 2020

Preprint

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Immunomodulatory agents dexamethasone and colchicine, antiviral drugs remdesivir, favipiravir and ribavirin, as well as antimalarial drugs chloroquine phosphate and hydroxychloroquine are currently used in the combat against COVID-19. However, whether some of these drugs have clinical efficacy for COVID-19 is under debate. Moreover, these drugs are applied in COVID-19 patients with little knowledge of genetic biomarkers, which will hurt patient outcome. To answer these questions, we designed a screen approach that could employ genome-wide sgRNA libraries to systematically uncover genes crucial for these drugs' action. Here we present our findings, including genes crucial for the import, export, metabolic activation and inactivation of remdesivir, as well as genes that regulate colchicine and dexamethasone's immunosuppressive effects. Our findings provide preliminary information for developing urgently needed genetic biomarkers for these drugs. Such biomarkers will help better interpret COVID-19 clinical trial data and point to how to stratify COVID-19 patients for proper treatment with these drugs.

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

Cited by 40 publications

References 50 publications

Metabolic dependencies and vulnerabilities in leukemia

Metabolic dependencies and vulnerabilities in leukemia

Strategies to Overcome Resistance Mechanisms in T-Cell Acute Lymphoblastic Leukemia

Genetic determinants of COVID-19 drug efficacy revealed by genome-wide CRISPR screens

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