TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomide-resistant patients

Caceres G.; McGraw K.; Yip B.H.Pellagatti A.Johnson J.Zhang L.Liu K.Zhang L.M.Fulp W.J.Lee J.-H.Al Ali N.H.Basiorka A.Smith L.J.Daugherty F.J.Littleton N.Wells R.A.Sokol L.Wei S.Komrokji R.S.Boultwood J.List A.F.

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TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomide-resistant patients

机译：TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomide-resistant patients

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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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《Proceedings of the National Academy of Sciences of the United States of America》 |2013年第40期|16127-16132|共6页
作者
Caceres G.; McGraw K.; Yip B.H.Pellagatti A.Johnson J.Zhang L.Liu K.Zhang L.M.Fulp W.J.Lee J.-H.Al Ali N.H.Basiorka A.Smith L.J.Daugherty F.J.Littleton N.Wells R.A.Sokol L.Wei S.Komrokji R.S.Boultwood J.List A.F.;
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作者单位

H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, United States;

Smith Holdings LLC, Omaha, NE 68114, United States;

Eleos Inc., Omaha, NE 68144, United StatesDepartment of Clinical Haematology, Provincial Hospital, Port Elizabeth 6000, South AfricaMDS Research Program, Sunnybrook Health Sciences Centre, Toronto, ON, M4N 3M5, CanadaNuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, John Radcliffe Hospital, Oxford OX3 9DU, United Kingdom;

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收录信息美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
原文格式 PDF
正文语种英语
中图分类自然科学总论;
关键词
suppression; erythropoiesis; precursors;

TP53 suppression promotes erythropoiesis in del(5q) MDS, suggesting a targeted therapeutic strategy in lenalidomide-resistant patients

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