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  1. Article ; Online: Genetics and mechanisms of NT5C2-driven chemotherapy resistance in relapsed ALL.

    Dieck, Chelsea L / Ferrando, Adolfo

    Blood

    2019  Volume 133, Issue 21, Page(s) 2263–2268

    Abstract: Mutations in the cytosolic 5' nucleotidase II ( ...

    Abstract Mutations in the cytosolic 5' nucleotidase II (
    MeSH term(s) 5'-Nucleotidase ; Cell Proliferation/drug effects ; Cell Proliferation/genetics ; Drug Resistance, Neoplasm/drug effects ; Drug Resistance, Neoplasm/genetics ; Humans ; Mercaptopurine/therapeutic use ; Mutation ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology
    Chemical Substances Neoplasm Proteins ; Mercaptopurine (E7WED276I5) ; 5'-Nucleotidase (EC 3.1.3.5) ; NT5C2 protein, human (EC 3.1.3.5)
    Language English
    Publishing date 2019-03-25
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood-2019-01-852392
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Pharmacologic Inhibition of NT5C2 Reverses Genetic and Nongenetic Drivers of 6-MP Resistance in Acute Lymphoblastic Leukemia.

    Reglero, Clara / Dieck, Chelsea L / Zask, Arie / Forouhar, Farhad / Laurent, Anouchka P / Lin, Wen-Hsuan W / Albero, Robert / Miller, Hannah I / Ma, Cindy / Gastier-Foster, Julie M / Loh, Mignon L / Tong, Liang / Stockwell, Brent R / Palomero, Teresa / Ferrando, Adolfo A

    Cancer discovery

    2022  Volume 12, Issue 11, Page(s) 2646–2665

    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 ... ...

    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.
    Significance: Relapse-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.
    MeSH term(s) Humans ; Mercaptopurine/pharmacology ; Mercaptopurine/therapeutic use ; 5'-Nucleotidase/genetics ; 5'-Nucleotidase/therapeutic use ; Drug Resistance, Neoplasm/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Antineoplastic Agents/therapeutic use ; Recurrence
    Chemical Substances Mercaptopurine (E7WED276I5) ; 5'-Nucleotidase (EC 3.1.3.5) ; Antineoplastic Agents ; NT5C2 protein, human (EC 3.1.3.5)
    Language English
    Publishing date 2022-08-19
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 2625242-9
    ISSN 2159-8290 ; 2159-8274
    ISSN (online) 2159-8290
    ISSN 2159-8274
    DOI 10.1158/2159-8290.CD-22-0010
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 6916: Show issues Location:
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  3. Article ; Online: Structure and Mechanisms of NT5C2 Mutations Driving Thiopurine Resistance in Relapsed Lymphoblastic Leukemia.

    Dieck, Chelsea L / Tzoneva, Gannie / Forouhar, Farhad / Carpenter, Zachary / Ambesi-Impiombato, Alberto / Sánchez-Martín, Marta / Kirschner-Schwabe, Renate / Lew, Scott / Seetharaman, Jayaraman / Tong, Liang / Ferrando, Adolfo A

    Cancer cell

    2018  Volume 34, Issue 1, Page(s) 136–147.e6

    Abstract: Activating mutations in the cytosolic 5'-nucleotidase II gene NT5C2 drive resistance to 6-mercaptopurine in acute lymphoblastic leukemia. Here we demonstrate that constitutively active NT5C2 mutations K359Q and L375F reconfigure the catalytic center for ... ...

    Abstract Activating mutations in the cytosolic 5'-nucleotidase II gene NT5C2 drive resistance to 6-mercaptopurine in acute lymphoblastic leukemia. Here we demonstrate that constitutively active NT5C2 mutations K359Q and L375F reconfigure the catalytic center for substrate access and catalysis in the absence of allosteric activator. In contrast, most relapse-associated mutations, which involve the arm segment and residues along the surface of the inter-monomeric cavity, disrupt a built-in switch-off mechanism responsible for turning off NT5C2. In addition, we show that the C-terminal acidic tail lost in the Q523X mutation functions to restrain NT5C2 activation. These results uncover dynamic mechanisms of enzyme regulation targeted by chemotherapy resistance-driving NT5C2 mutations, with important implications for the development of NT5C2 inhibitor therapies.
    MeSH term(s) 5'-Nucleotidase/chemistry ; 5'-Nucleotidase/genetics ; 5'-Nucleotidase/metabolism ; Allosteric Regulation ; Animals ; Antimetabolites, Antineoplastic/pharmacology ; Catalytic Domain ; Drug Resistance, Neoplasm/genetics ; Gene Expression Regulation, Leukemic ; HEK293 Cells ; Humans ; Jurkat Cells ; Mercaptopurine/pharmacology ; Mice, Inbred C57BL ; Models, Molecular ; Mutation ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/enzymology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Protein Conformation, alpha-Helical ; Recurrence ; Structure-Activity Relationship
    Chemical Substances Antimetabolites, Antineoplastic ; Mercaptopurine (E7WED276I5) ; 5'-Nucleotidase (EC 3.1.3.5) ; NT5C2 protein, human (EC 3.1.3.5)
    Language English
    Publishing date 2018-07-07
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
    ZDB-ID 2078448-X
    ISSN 1878-3686 ; 1535-6108
    ISSN (online) 1878-3686
    ISSN 1535-6108
    DOI 10.1016/j.ccell.2018.06.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.MG 104: Show issues

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  4. Article ; Online: In vitro modeling of endothelial interaction with macrophages and pericytes demonstrates Notch signaling function in the vascular microenvironment.

    Tattersall, Ian W / Du, Jing / Cong, Zhuangzhuang / Cho, Bennet S / Klein, Alyssa M / Dieck, Chelsea L / Chaudhri, Reyhaan A / Cuervo, Henar / Herts, James H / Kitajewski, Jan

    Angiogenesis

    2016  Volume 19, Issue 2, Page(s) 201–215

    Abstract: Angiogenesis is regulated by complex interactions between endothelial cells and support cells of the vascular microenvironment, such as tissue myeloid cells and vascular mural cells. Multicellular interactions during angiogenesis are difficult to study ... ...

    Abstract Angiogenesis is regulated by complex interactions between endothelial cells and support cells of the vascular microenvironment, such as tissue myeloid cells and vascular mural cells. Multicellular interactions during angiogenesis are difficult to study in animals and challenging in a reductive setting. We incorporated stromal cells into an established bead-based capillary sprouting assay to develop assays that faithfully reproduce major steps of vessel sprouting and maturation. We observed that macrophages enhance angiogenesis, increasing the number and length of endothelial sprouts, a property we have dubbed "angiotrophism." We found that polarizing macrophages toward a pro-inflammatory profile further increased their angiotrophic stimulation of vessel sprouting, and this increase was dependent on macrophage Notch signaling. To study endothelial/pericyte interactions, we added vascular pericytes directly to the bead-bound endothelial monolayer. These pericytes formed close associations with the endothelial sprouts, causing increased sprout number and vessel caliber. We found that Jagged1 expression and Notch signaling are essential for the growth of both endothelial cells and pericytes and may function in their interaction. We observed that combining endothelial cells with both macrophages and pericytes in the same sprouting assay has multiplicative effects on sprouting. These results significantly improve bead-capillary sprouting assays and provide an enhanced method for modeling interactions between the endothelium and the vascular microenvironment. Achieving this in a reductive in vitro setting represents a significant step toward a better understanding of the cellular elements that contribute to the formation of mature vasculature.
    MeSH term(s) Animals ; Cell Communication ; Cell Line ; Cell Polarity ; Cell Survival ; Cellular Microenvironment ; Coculture Techniques ; Gene Knockdown Techniques ; Human Umbilical Vein Endothelial Cells/cytology ; Human Umbilical Vein Endothelial Cells/metabolism ; Humans ; Inflammation/pathology ; Inflammation Mediators/metabolism ; Macrophages/cytology ; Macrophages/metabolism ; Mice ; Models, Biological ; Myeloid Cells/cytology ; Myeloid Cells/metabolism ; Neovascularization, Physiologic ; Pericytes/cytology ; Pericytes/metabolism ; Receptors, Notch/metabolism ; Serrate-Jagged Proteins/metabolism ; Signal Transduction
    Chemical Substances Inflammation Mediators ; Receptors, Notch ; Serrate-Jagged Proteins
    Language English
    Publishing date 2016-04
    Publishing country Germany
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 1484717-6
    ISSN 1573-7209 ; 0969-6970
    ISSN (online) 1573-7209
    ISSN 0969-6970
    DOI 10.1007/s10456-016-9501-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    Zs.A 5094: Show issues Location:
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  5. Article ; Online: Clonal evolution mechanisms in NT5C2 mutant-relapsed acute lymphoblastic leukaemia.

    Tzoneva, Gannie / Dieck, Chelsea L / Oshima, Koichi / Ambesi-Impiombato, Alberto / Sánchez-Martín, Marta / Madubata, Chioma J / Khiabanian, Hossein / Yu, Jiangyan / Waanders, Esme / Iacobucci, Ilaria / Sulis, Maria Luisa / Kato, Motohiro / Koh, Katsuyoshi / Paganin, Maddalena / Basso, Giuseppe / Gastier-Foster, Julie M / Loh, Mignon L / Kirschner-Schwabe, Renate / Mullighan, Charles G /
    Rabadan, Raul / Ferrando, Adolfo A

    Nature

    2018  Volume 553, Issue 7689, Page(s) 511–514

    Abstract: Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis. Gain-of-function mutations in the 5'-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present ... ...

    Abstract Relapsed acute lymphoblastic leukaemia (ALL) is associated with resistance to chemotherapy and poor prognosis. Gain-of-function mutations in the 5'-nucleotidase, cytosolic II (NT5C2) gene induce resistance to 6-mercaptopurine and are selectively present in relapsed ALL. Yet, the mechanisms involved in NT5C2 mutation-driven clonal evolution during the initiation of leukaemia, disease progression and relapse remain unknown. Here we use a conditional-and-inducible leukaemia model to demonstrate that expression of NT5C2(R367Q), a highly prevalent relapsed-ALL NT5C2 mutation, induces resistance to chemotherapy with 6-mercaptopurine at the cost of impaired leukaemia cell growth and leukaemia-initiating cell activity. The loss-of-fitness phenotype of NT5C2
    MeSH term(s) 5'-Nucleotidase/genetics ; 5'-Nucleotidase/metabolism ; Animals ; Cell Proliferation ; Clonal Evolution ; Disease Models, Animal ; Drug Resistance, Neoplasm/genetics ; Female ; Gain of Function Mutation/genetics ; Guanosine/biosynthesis ; HEK293 Cells ; Humans ; IMP Dehydrogenase/antagonists & inhibitors ; IMP Dehydrogenase/metabolism ; Male ; Mercaptopurine/pharmacology ; Mercaptopurine/therapeutic use ; Mice ; Mutation/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/pathology ; Purines/metabolism ; Receptor, Notch1/metabolism ; Recurrence ; Xenograft Model Antitumor Assays
    Chemical Substances Notch1 protein, mouse ; Purines ; Receptor, Notch1 ; Guanosine (12133JR80S) ; Mercaptopurine (E7WED276I5) ; IMP Dehydrogenase (EC 1.1.1.205) ; 5'-Nucleotidase (EC 3.1.3.5) ; NT5C2 protein, human (EC 3.1.3.5) ; purine (W60KTZ3IZY)
    Language English
    Publishing date 2018-01-17
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 120714-3
    ISSN 1476-4687 ; 0028-0836
    ISSN (online) 1476-4687
    ISSN 0028-0836
    DOI 10.1038/nature25186
    Database MEDical Literature Analysis and Retrieval System OnLINE

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