دورية أكاديمية
A stem cell epigenome is associated with primary nonresponse to CD19 CAR T cells in pediatric acute lymphoblastic leukemia.
| العنوان: | A stem cell epigenome is associated with primary nonresponse to CD19 CAR T cells in pediatric acute lymphoblastic leukemia. |
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| المؤلفون: | Masih, Katherine E, Gardner, Rebecca A, Chou, Hsien-Chao, Abdelmaksoud, Abdalla, Song, Young K, Mariani, Luca, Gangalapudi, Vineela, Gryder, Berkley E, Wilson, Ashley L, Adebola, Serifat O, Stanton, Benjamin Z, Wang, Chaoyu, Milewski, David, Kim, Yong Yean, Tian, Meijie, Cheuk, Adam Tai-Chi, Wen, Xinyu, Zhang, Yue, Altan-Bonnet, Grégoire, Kelly, Michael C, Wei, Jun S, Bulyk, Martha L, Jensen, Michael C, Orentas, Rimas J, Khan, Javed |
| المصدر: | Blood Adv ; ISSN:2473-9537 ; Volume:7 ; Issue:15 |
| بيانات النشر: | Silverchair Information Systems |
| سنة النشر: | 2023 |
| المجموعة: | PubMed Central (PMC) |
| الوصف: | CD19 chimeric antigen receptor T-cell therapy (CD19-CAR) has changed the treatment landscape and outcomes for patients with pre-B-cell acute lymphoblastic leukemia (B-ALL). Unfortunately, primary nonresponse (PNR), sustained CD19+ disease, and concurrent expansion of CD19-CAR occur in 20% of the patients and is associated with adverse outcomes. Although some failures may be attributable to CD19 loss, mechanisms of CD19-independent, leukemia-intrinsic resistance to CD19-CAR remain poorly understood. We hypothesize that PNR leukemias are distinct compared with primary sensitive (PS) leukemias and that these differences are present before treatment. We used a multiomic approach to investigate this in 14 patients (7 with PNR and 7 with PS) enrolled in the PLAT-02 trial at Seattle Children's Hospital. Long-read PacBio sequencing helped identify 1 PNR in which 47% of CD19 transcripts had exon 2 skipping, but other samples lacked CD19 transcript abnormalities. Epigenetic profiling discovered DNA hypermethylation at genes targeted by polycomb repressive complex 2 (PRC2) in embryonic stem cells. Similarly, assays of transposase-accessible chromatin-sequencing revealed reduced accessibility at these PRC2 target genes, with a gain in accessibility of regions characteristic of hematopoietic stem cells and multilineage progenitors in PNR. Single-cell RNA sequencing and cytometry by time of flight analyses identified leukemic subpopulations expressing multilineage markers and decreased antigen presentation in PNR. We thus describe the association of a stem cell epigenome with primary resistance to CD19-CAR therapy. Future trials incorporating these biomarkers, with the addition of multispecific CAR T cells targeting against leukemic stem cell or myeloid antigens, and/or combined epigenetic therapy to disrupt this distinct stem cell epigenome may improve outcomes of patients with B-ALL. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| العلاقة: | https://doi.org/10.1182/bloodadvances.2022008977Test; https://pubmed.ncbi.nlm.nih.gov/36607839Test; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440404Test/ |
| DOI: | 10.1182/bloodadvances.2022008977 |
| الإتاحة: | https://doi.org/10.1182/bloodadvances.2022008977Test https://pubmed.ncbi.nlm.nih.gov/36607839Test https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10440404Test/ |
| حقوق: | © 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. |
| رقم الانضمام: | edsbas.BB223EA6 |
| قاعدة البيانات: | BASE |
| DOI: | 10.1182/bloodadvances.2022008977 |
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