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  1. Article ; Online: Pharmacogenomics and ALL treatment: How to optimize therapy.

    Karol, Seth E / Yang, Jun J

    Seminars in hematology

    2020  Volume 57, Issue 3, Page(s) 130–136

    Abstract: Inherited genetic variations may alter drug sensitivity in patients with acute lymphoblastic leukemia, predisposing to adverse treatment side effects. In this review, we discuss evidence from children and young adults with acute lymphoblastic leukemia to ...

    Abstract Inherited genetic variations may alter drug sensitivity in patients with acute lymphoblastic leukemia, predisposing to adverse treatment side effects. In this review, we discuss evidence from children and young adults with acute lymphoblastic leukemia to review the available pharmacogenomic data with an emphasis on clinically actionable and emerging discoveries, for example, genetic variants in thiopurine methyltransferase and NUDT15 that alter 6-mercaptopurine dosing. We also highlight the need for ongoing pharmacogenomic research to validate the significance of recent findings. Further research in young adults, as well as with novel therapeutics, is needed to provide optimal therapy in future trials.
    MeSH term(s) Humans ; Pharmacogenetics/methods ; Precision Medicine/methods ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/therapy
    Language English
    Publishing date 2020-10-20
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 206923-4
    ISSN 1532-8686 ; 0037-1963
    ISSN (online) 1532-8686
    ISSN 0037-1963
    DOI 10.1053/j.seminhematol.2020.10.001
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  2. Article ; Online: Maintenance therapy for acute lymphoblastic leukemia: basic science and clinical translations.

    Toksvang, Linea N / Lee, Shawn H R / Yang, Jun J / Schmiegelow, Kjeld

    Leukemia

    2022  Volume 36, Issue 7, Page(s) 1749–1758

    Abstract: Maintenance therapy (MT) with oral methotrexate (MTX) and 6-mercaptopurine (6-MP) is essential for the cure of acute lymphoblastic leukemia (ALL). MTX and 6-MP interfere with nucleotide synthesis and salvage pathways. The primary cytotoxic mechanism ... ...

    Abstract Maintenance therapy (MT) with oral methotrexate (MTX) and 6-mercaptopurine (6-MP) is essential for the cure of acute lymphoblastic leukemia (ALL). MTX and 6-MP interfere with nucleotide synthesis and salvage pathways. The primary cytotoxic mechanism involves the incorporation of thioguanine nucleotides (TGNs) into DNA (as DNA-TG), which may be enhanced by the inhibition of de novo purine synthesis by other MTX/6-MP metabolites. Co-medication during MT is common. Although Pneumocystis jirovecii prophylaxis appears safe, the benefit of glucocorticosteroid/vincristine pulses in improving survival and of allopurinol to moderate 6-MP pharmacokinetics remains uncertain. Numerous genetic polymorphisms influence the pharmacology, efficacy, and toxicity (mainly myelosuppression and hepatotoxicity) of MTX and thiopurines. Thiopurine S-methyltransferase (encoded by TPMT) decreases TGNs but increases methylated 6-MP metabolites (MeMPs); similarly, nudix hydrolase 15 (encoded by NUDT15) also decreases TGNs available for DNA incorporation. Loss-of-function variants in both genes are currently used to guide MT, but do not fully explain the inter-patient variability in thiopurine toxicity. Because of the large inter-individual variations in MTX/6-MP bioavailability and metabolism, dose adjustments are traditionally guided by the degree of myelosuppression, but this does not accurately reflect treatment intensity. DNA-TG is a common downstream metabolite of MTX/6-MP combination chemotherapy, and a higher level of DNA-TG has been associated with a lower relapse hazard, leading to the development of the Thiopurine Enhanced ALL Maintenance (TEAM) strategy-the addition of low-dose (2.5-12.5 mg/m
    MeSH term(s) Humans ; Mercaptopurine ; Methotrexate/therapeutic use ; Methyltransferases/genetics ; Methyltransferases/metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/drug therapy ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/metabolism ; Recurrence ; Thioguanine/therapeutic use
    Chemical Substances Mercaptopurine (E7WED276I5) ; Methyltransferases (EC 2.1.1.-) ; Thioguanine (FTK8U1GZNX) ; Methotrexate (YL5FZ2Y5U1)
    Language English
    Publishing date 2022-06-02
    Publishing country England
    Document type Journal Article ; Review ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
    ZDB-ID 807030-1
    ISSN 1476-5551 ; 0887-6924
    ISSN (online) 1476-5551
    ISSN 0887-6924
    DOI 10.1038/s41375-022-01591-4
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  3. Article ; Online: Genetic defects in hematopoietic transcription factors and predisposition to acute lymphoblastic leukemia.

    Gocho, Yoshihiro / Yang, Jun J

    Blood

    2019  Volume 134, Issue 10, Page(s) 793–797

    Abstract: Recent genome-wide studies have revealed a plethora of germline variants that significantly influence the susceptibility to acute lymphoblastic leukemia (ALL), thus providing compelling evidence for genetic inheritance of this blood cancer. In particular, ...

    Abstract Recent genome-wide studies have revealed a plethora of germline variants that significantly influence the susceptibility to acute lymphoblastic leukemia (ALL), thus providing compelling evidence for genetic inheritance of this blood cancer. In particular, hematopoietic transcription factors (eg, ETV6, PAX5, IKZF1) are most frequently implicated in familial ALL, and germline variants in these genes confer strong predisposition (albeit with incomplete penetrance). Studies of germline risk factors for ALL provide unique insights into the molecular etiology of this leukemia.
    MeSH term(s) Genetic Predisposition to Disease ; Germ-Line Mutation ; Hematopoiesis/genetics ; Hematopoietic System/metabolism ; Hematopoietic System/physiology ; Humans ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/blood ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Risk Factors ; Transcription Factors/genetics ; Transcription Factors/metabolism
    Chemical Substances Transcription Factors
    Language English
    Publishing date 2019-07-16
    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.2018852400
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  4. Article ; Online: Pharmacogenomics for Drug Dosing in Children: Current Use, Knowledge, and Gaps.

    Hoshitsuki, Keito / Fernandez, Christian A / Yang, Jun J

    Journal of clinical pharmacology

    2021  Volume 61 Suppl 1, Page(s) S188–S192

    Abstract: Pharmacogenomics research ranges from the discovery of genetic factors to explain interpatient variability in drug exposure and response to clinical implementation of this knowledge to improve pharmacotherapy. Medications with actionable pharmacogenomic ... ...

    Abstract Pharmacogenomics research ranges from the discovery of genetic factors to explain interpatient variability in drug exposure and response to clinical implementation of this knowledge to improve pharmacotherapy. Medications with actionable pharmacogenomic associations are frequently used in children, and therefore pharmacogenomics-guided precision medicine is readily applicable to the pediatric population. Although heritable genetics are considered immutable, the impact of genetic variation in pharmacogenes is modified by other factors such as age-dependent changes in gene expression. Early evidence has emerged indicating that the interaction between ontogeny and pharmacogenomics determines whether or how genetics-based dosing algorithms should be adjusted in children versus adults. However, there is still a paucity of data describing pharmacogenomic associations in patient populations across the life span. Future research is much needed to evaluate the impact of pharmacogenomics on drug dosing specific to the pediatric population, along with consideration of other developmental and physiological factors uniquely related to drug disposition in this population.
    MeSH term(s) Child ; Drug Dosage Calculations ; Humans ; Pharmaceutical Preparations/administration & dosage ; Pharmaceutical Preparations/metabolism ; Pharmacogenetics ; Precision Medicine/methods
    Chemical Substances Pharmaceutical Preparations
    Language English
    Publishing date 2021-06-29
    Publishing country England
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 188980-1
    ISSN 1552-4604 ; 0091-2700 ; 0021-9754
    ISSN (online) 1552-4604
    ISSN 0091-2700 ; 0021-9754
    DOI 10.1002/jcph.1891
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  5. Article ; Online: ARID5B

    Goodings, Charnise / Zhao, Xujie / McKinney-Freeman, Shannon / Zhang, Hui / Yang, Jun J

    Haematologica

    2023  Volume 108, Issue 2, Page(s) 502–512

    Abstract: There is growing evidence for an inherited basis of susceptibility to childhood acute lymphoblastic leukemia. Genomewide association studies by us and others have identified non-coding acute lymphoblastic leukemia risk variants at the ARID5B gene locus, ... ...

    Abstract There is growing evidence for an inherited basis of susceptibility to childhood acute lymphoblastic leukemia. Genomewide association studies by us and others have identified non-coding acute lymphoblastic leukemia risk variants at the ARID5B gene locus, but the molecular mechanisms linking ARID5B to normal and malignant hematopoiesis remain largely unknown. Using a Vav1-driven transgenic mouse model, we characterized the role of Arid5b in hematopoiesis in vivo. Arid5b overexpression resulted in a dramatic reduction in the proportion of circulating B cells, immature, and mature Bcell fractions in the peripheral blood and the bone marrow, and also a decrease of follicular B cells in the spleen. There were significant defects in B-cell activation upon Arid5b overexpression in vitro with hyperactivation of B-cell receptor signaling at baseline. In addition, increased mitochondrial oxygen consumption rate of naïve or stimulated B cells of Arid5b-overexpressing mice was observed, compared to the rate of wild-type counterparts. Taken together, our results indicate that ARID5B may play an important role in B-cell development and function.
    MeSH term(s) Animals ; Mice ; Transcription Factors/genetics ; DNA-Binding Proteins/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Genome-Wide Association Study ; Hematopoiesis
    Chemical Substances Transcription Factors ; DNA-Binding Proteins ; Arid5b protein, mouse
    Language English
    Publishing date 2023-02-01
    Publishing country Italy
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2333-4
    ISSN 1592-8721 ; 0017-6567 ; 0390-6078
    ISSN (online) 1592-8721
    ISSN 0017-6567 ; 0390-6078
    DOI 10.3324/haematol.2022.281157
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  6. Article ; Online: ARID5B

    Goodings, Charnise / Zhao, Xujie / McKinney-Freeman, Shannon / Zhang, Hui / Yang, Jun J

    Haematologica

    2023  Volume 108, Issue 10, Page(s) 2877

    Language English
    Publishing date 2023-10-01
    Publishing country Italy
    Document type Journal Article
    ZDB-ID 2333-4
    ISSN 1592-8721 ; 0017-6567 ; 0390-6078
    ISSN (online) 1592-8721
    ISSN 0017-6567 ; 0390-6078
    DOI 10.3324/haematol.2023.283687
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  7. Article ; Online: PharmGKB summary: acyclovir/ganciclovir pathway.

    Maillard, Maud / Gong, Li / Nishii, Rina / Yang, Jun J / Whirl-Carrillo, Michelle / Klein, Teri E

    Pharmacogenetics and genomics

    2022  Volume 32, Issue 5, Page(s) 201–208

    MeSH term(s) Acyclovir/therapeutic use ; Antiviral Agents/therapeutic use ; Ganciclovir ; Humans
    Chemical Substances Antiviral Agents ; Ganciclovir (P9G3CKZ4P5) ; Acyclovir (X4HES1O11F)
    Language English
    Publishing date 2022-05-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural
    ZDB-ID 2175826-8
    ISSN 1744-6880 ; 0960-314X ; 1744-6872
    ISSN (online) 1744-6880
    ISSN 0960-314X ; 1744-6872
    DOI 10.1097/FPC.0000000000000474
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  8. Article: Bayesian modelling of response to therapy and drug-sensitivity in acute lymphoblastic leukemia.

    Cremaschi, Andrea / Yang, Wenjian / De Iorio, Maria / Evans, William E / Yang, Jun J / Rosner, Gary L

    Research square

    2023  

    Abstract: Acute lymphoblastic leukemia (ALL) is a heterogeneous haematologic malignancy involving the abnormal proliferation of immature lymphocytes and accounts for most paediatric cancer cases. The management of ALL in children has seen great improvement in the ... ...

    Abstract Acute lymphoblastic leukemia (ALL) is a heterogeneous haematologic malignancy involving the abnormal proliferation of immature lymphocytes and accounts for most paediatric cancer cases. The management of ALL in children has seen great improvement in the last decades thanks to greater understanding of the disease leading to improved treatment strategies evidenced through clinical trials. Common therapy regimens involve a first course of chemotherapy (induction phase), followed by treatment with a combination of anti-leukemia drugs. A measure of the efficacy early in the course of therapy is the presence of minimal residual disease (MRD). MRD quantifies residual tumor cells and indicates the effiectiveness of the treatment over the course of therapy. MRD positivity is defined for values of MRD greater than 0.01%, yielding left-censored MRD observations. We propose a Bayesian model to study the relationship between patient features (leukemia subtype, baseline characteristics, and drug sensitivity profile) and MRD observed at two time points during the induction phase. Specifically, we model the observed MRD values via an auto-regressive model, accounting for left-censoring of the data and for the fact that some patients are already in remission after the first stage of induction therapy. Patient characteristics are included in the model via linear regression terms. In particular, patient-specific drug sensitivity based on
    Language English
    Publishing date 2023-02-24
    Publishing country United States
    Document type Preprint
    DOI 10.21203/rs.3.rs-2542277/v1
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  9. Article ; Online: Monitoring drug metabolic pathways through extracellular vesicles in mouse plasma.

    Wu, Xiaofeng / Quan, Menchus / Hadisurya, Marco / Hu, Jianzhong / Liu, Yi-Kai / Zhuang, Yuxin / Li, Li / Iliuk, Anton B / Yang, Jun J / Kuang, Shihuan / Tao, W Andy

    PNAS nexus

    2024  Volume 3, Issue 2, Page(s) pgae023

    Abstract: The ability to monitor the response of metabolic enzymes to drug exposure in individuals is highly appealing and critical to personalized medicine. Although pharmacogenomics assesses genotypic differences, it does not report changes in metabolic enzyme ... ...

    Abstract The ability to monitor the response of metabolic enzymes to drug exposure in individuals is highly appealing and critical to personalized medicine. Although pharmacogenomics assesses genotypic differences, it does not report changes in metabolic enzyme activities due to environmental factors such as drug interactions. Here, we report a quantitative proteomics strategy to monitor drug metabolic pathways by profiling metabolic enzymes in circulating extracellular vesicles (EVs) upon drug exposure. Mass spectrometry (MS)-based measurement revealed that changes in metabolic enzyme abundance in EVs paralleled those in hepatic cells isolated from liver tissue. Coupling with multiplexed isotopic labeling, we temporally quantified 34 proteins involved in drug absorption, distribution, metabolism, and excretion (ADME) pathways. Out of 44 known ADME proteins in plasma EVs, previously annotated mouse cytochrome P450 3A11 (Cyp3a11), homolog to human CYP3A4, and uridine 5'-diphospho (UDP) glucuronosyltransferase 2A3 (Ugt2a3), increased upon daily rifampicin dosage. Dasatinib, a tyrosine kinase inhibitor to treat leukemia, also elevated Cyp3a11 levels in plasma EVs, but to a lesser extent. Altogether, this study demonstrates that measuring drug enzymes in circulating EVs as an effective surrogate is highly feasible and may transform today's drug discovery and development for personalized medicine.
    Language English
    Publishing date 2024-01-23
    Publishing country England
    Document type Journal Article
    ISSN 2752-6542
    ISSN (online) 2752-6542
    DOI 10.1093/pnasnexus/pgae023
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  10. Article ; Online: The Promise and the Reality of Genomics to Guide Precision Medicine in Pediatric Oncology: The Decade Ahead.

    Evans, William E / Pui, Ching-Hon / Yang, Jun J

    Clinical pharmacology and therapeutics

    2019  Volume 107, Issue 1, Page(s) 176–180

    Abstract: Much has been written about the promise of "precision medicine," especially in oncology, where somatic mutations can influence the response of cancer cells to "targeted therapy." There have been successful examples of targeted therapy improving the ... ...

    Abstract Much has been written about the promise of "precision medicine," especially in oncology, where somatic mutations can influence the response of cancer cells to "targeted therapy." There have been successful examples of targeted therapy improving the outcome of some childhood cancers, such as the addition of an ABL class tyrosine kinase inhibitor to conventional chemotherapy substantially improving the cure rate for patients with BCR-ABL1 positive acute lymphoblastic leukemia. Although there are other mutations serving as putative targets in various childhood leukemias and solid tumors, effective targeted therapy has yet to be established for them in prospective clinical trials. There are also uncertainties about which "targeted therapy" to use when patients have multiple targetable genomic lesions in their cancer cells, given the paucity of data upon which to develop evidence-based guidelines for selecting and integrating targeted agents for individual patients. There are also multiple examples of inherited germline variants for which evidence-based guidelines have been developed by the Clinical Pharmacogenetics Implementation Consortium to guide the selection and dosing of medications in children with cancer. Clinical pharmacology is poised to play a critical role in both the discovery and development of new targeted anticancer agents and their evidence-based translation into better treatment for children with cancer. To embrace these challenges and opportunities of "precision medicine," clinical and basic pharmacologists must expand the depth of our science and the bandwidth of our translational capacity if we are to optimize precision medicine and advance the treatment of cancer in children and adults.
    MeSH term(s) Antineoplastic Agents/administration & dosage ; Antineoplastic Agents/pharmacology ; Child ; Dose-Response Relationship, Drug ; Humans ; Molecular Targeted Therapy ; Neoplasms/drug therapy ; Neoplasms/genetics ; Neoplasms/pathology ; Pharmacogenetics ; Practice Guidelines as Topic ; Precision Medicine/methods
    Chemical Substances Antineoplastic Agents
    Language English
    Publishing date 2019-11-14
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 123793-7
    ISSN 1532-6535 ; 0009-9236
    ISSN (online) 1532-6535
    ISSN 0009-9236
    DOI 10.1002/cpt.1660
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