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Analysis of institutional authors

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May 22, 2024
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Pharmacologic Inhibition of NT5C2 Reverses Genetic and Nongenetic Drivers of 6-MP Resistance in Acute Lymphoblastic Leukemia.

Publicated to: Cancer Discovery. 12 (11): 2646-2665 - 2022-11-01 12(11), DOI: 10.1158/2159-8290.cd-22-0010

Authors:

Reglero C; Dieck CL; Zask A; Forouhar F; Laurent AP; Lin WW; Albero R; Miller HI; Ma C; Gastier-Foster JM; Loh ML; Tong L; Stockwell BR; Palomero T; Ferrando AA
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Affiliations

Department of Biological Sciences and Department of Chemistry, Columbia University, New York, New York. - Author
Department of Biological Sciences, Northeast Structural Genomics Consortium, Columbia University, New York, New York. - Author
Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York. - Author
Department of Pediatrics, Baylor College of Medicine, Houston, Texas.; Children's Oncology Group, Arcadia, California. - Author
Division of Hematology, Oncology, Bone Marrow Transplant, and Cellular Therapies, Seattle Children's Hospital, University of Washington, Seattle, Washington. - Author
Institute for Cancer Genetics, Columbia University, New York, New York. - Author
Institute for Cancer Genetics, Columbia University, New York, New York.; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York. - Author
Institute for Cancer Genetics, Columbia University, New York, New York.; Department of Pathology and Cell Biology, Columbia University Medical Center, New York, New York.; Department of Pediatrics, Columbia University Medical Center, New York, New York.; - Author
Proteomics and Macromolecular Crystallography Shared Resource, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York. - Author
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Abstract

Low-intensity maintenance therapy with 6-mercaptopurine (6-MP) limits the occurrence of acute lymphoblastic leukemia (ALL) relapse and is central to the success of multiagent chemotherapy protocols. Activating mutations in the 5'-nucleotidase cytosolic II (NT5C2) gene drive resistance to 6-MP in over 35% of early relapse ALL cases. Here we identify CRCD2 as a first-in-class small-molecule NT5C2 nucleotidase inhibitor broadly active against leukemias bearing highly prevalent relapse-associated mutant forms of NT5C2 in vitro and in vivo. Importantly, CRCD2 treatment also enhanced the cytotoxic activity of 6-MP in NT5C2 wild-type leukemias, leading to the identification of NT5C2 Ser502 phosphorylation as a novel NT5C2-mediated mechanism of 6-MP resistance in this disease. These results uncover an unanticipated role of nongenetic NT5C2 activation as a driver of 6-MP resistance in ALL and demonstrate the potential of NT5C2 inhibitor therapy for enhancing the efficacy of thiopurine maintenance therapy and overcoming resistance at relapse.SignificanceRelapse-associated NT5C2 mutations directly contribute to relapse in ALL by driving resistance to chemotherapy with 6-MP. Pharmacologic inhibition of NT5C2 with CRCD2, a first-in-class nucleotidase inhibitor, enhances the cytotoxic effects of 6-MP and effectively reverses thiopurine resistance mediated by genetic and nongenetic mechanisms of NT5C2 activation in ALL. This article is highlighted in the In This Issue feature, p. 2483.
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Keywords

5'-nucleotidaseAntineoplastic agentsDrug resistance, neoplasmHumansMercaptopurinePrecursor cell lymphoblastic leukemia-lymphomaRecurrence

Quality index

Bibliometric impact. Analysis of the contribution and dissemination channel

The work has been published in the journal Cancer Discovery due to its progression and the good impact it has achieved in recent years, according to the agency WoS (JCR), it has become a reference in its field. In the year of publication of the work, 2022, it was in position 9/241, thus managing to position itself as a Q1 (Primer Cuartil), in the category Oncology. Notably, the journal is positioned above the 90th percentile.

Independientemente del impacto esperado determinado por el canal de difusión, es importante destacar el impacto real observado de la propia aportación.

Según las diferentes agencias de indexación, el número de citas acumuladas por esta publicación hasta la fecha 2026-01-02:

  • Europe PMC: 4
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Impact and social visibility

From the perspective of influence or social adoption, and based on metrics associated with mentions and interactions provided by agencies specializing in calculating the so-called "Alternative or Social Metrics," we can highlight as of 2026-01-02:

  • The use, from an academic perspective evidenced by the Altmetric agency indicator referring to aggregations made by the personal bibliographic manager Mendeley, gives us a total of: 15.
  • The use of this contribution in bookmarks, code forks, additions to favorite lists for recurrent reading, as well as general views, indicates that someone is using the publication as a basis for their current work. This may be a notable indicator of future more formal and academic citations. This claim is supported by the result of the "Capture" indicator, which yields a total of: 17 (PlumX).

With a more dissemination-oriented intent and targeting more general audiences, we can observe other more global scores such as:

  • The Total Score from Altmetric: 13.
  • The number of mentions on the social network X (formerly Twitter): 17 (Altmetric).
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Leadership analysis of institutional authors

This work has been carried out with international collaboration, specifically with researchers from: United States of America.

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