دورية أكاديمية
TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomide-resistant patients.
| العنوان: | TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomide-resistant patients. |
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| المؤلفون: | Caceres G; H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612., McGraw K, Yip BH, Pellagatti A, Johnson J, Zhang L, Liu K, Zhang LM, Fulp WJ, Lee JH, Al Ali NH, Basiorka A, Smith LJ, Daugherty FJ, Littleton N, Wells RA, Sokol L, Wei S, Komrokji RS, Boultwood J, List AF |
| المصدر: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2013 Oct 01; Vol. 110 (40), pp. 16127-32. Date of Electronic Publication: 2013 Sep 16. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Washington, DC : National Academy of Sciences |
| مواضيع طبية MeSH: | Erythropoiesis/*drug effects , Myelodysplastic Syndromes/*metabolism , Oligonucleotides/*pharmacology , Tumor Suppressor Protein p53/*antagonists & inhibitors, Base Sequence ; Dexamethasone ; Drug Resistance/physiology ; Erythroid Precursor Cells/drug effects ; Flow Cytometry ; Fluorescent Antibody Technique ; Humans ; Immunohistochemistry ; In Situ Hybridization, Fluorescence ; Lenalidomide ; Molecular Sequence Data ; Myelodysplastic Syndromes/genetics ; Oligonucleotides/genetics ; Real-Time Polymerase Chain Reaction ; Sequence Analysis, DNA ; Statistics, Nonparametric ; Thalidomide/analogs & derivatives ; Treatment Outcome ; Tumor Suppressor Protein p53/genetics ; Tumor Suppressor Protein p53/metabolism |
| مستخلص: | Stabilization of p53 in erythroid precursors in response to nucleosomal stress underlies the hypoplastic anemia in myelodysplastic syndromes (MDS) with chromosome 5q deletion [del(5q)]. We investigated whether cenersen, a clinically active 20-mer antisense oligonucleotide complementary to TP53 exon10, could suppress p53 expression and restore erythropoiesis in del(5q) MDS. Cenersen treatment of ribosomal protein S-14-deficient erythroblasts significantly reduced cellular p53 and p53-up-regulated modulator of apoptosis expression compared with controls, accompanied by a significant reduction in apoptosis and increased cell proliferation. In a two-stage erythroid differentiation assay, cenersen significantly suppressed nuclear p53 in bone marrow CD34+ cells isolated from patients with del(5q) MDS, whereas erythroid burst recovery increased proportionally to the magnitude of p53 suppression without evidence of del(5q) clonal suppression (r = -0.6; P = 0.005). To explore the effect of p53 suppression on erythropoiesis in vivo, dexamethasone, a glucocorticoid receptor-dependent p53 antagonist, was added to lenalidomide treatment in eight lower-risk, transfusion-dependent, del(5q) MDS patients with acquired drug resistance. Transfusion independence was restored in five patients accompanied by expansion of erythroid precursors and decreased cellular p53 expression. We conclude that targeted suppression of p53 could support effective erythropoiesis in lenalidomide-resistant del(5q) MDS. |
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| معلومات مُعتمدة: | P30 CA076292 United States CA NCI NIH HHS; RP-PG-0310-1004 United Kingdom DH_ Department of Health; 5R01 CA-13107604 United States CA NCI NIH HHS |
| المشرفين على المادة: | 0 (Oligonucleotides) 0 (Tumor Suppressor Protein p53) 4Z8R6ORS6L (Thalidomide) 7S5I7G3JQL (Dexamethasone) 872847-66-0 (cenersen) F0P408N6V4 (Lenalidomide) |
| تواريخ الأحداث: | Date Created: 20130918 Date Completed: 20131203 Latest Revision: 20220129 |
| رمز التحديث: | 20240628 |
| مُعرف محوري في PubMed: | PMC3791697 |
| DOI: | 10.1073/pnas.1311055110 |
| PMID: | 24043769 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1091-6490 |
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| DOI: | 10.1073/pnas.1311055110 |