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DOI | 10.1182/blood-2011-06-359075 |
Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL | |
Decker, Sarah1,2; Zirlik, Katja1; Djebatchie, Lauritte1; Hartmann, David1; Ihorst, Gabriele3; Schmitt-Graeff, Annette4; Herchenbach, Dieter1; Jumaa, Hassan2; Warmuth, Markus5; Veelken, Hendrik1,6; Dierks, Christine1 | |
通讯作者 | Dierks, Christine |
来源期刊 | BLOOD
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ISSN | 0006-4971 |
出版年 | 2012 |
卷号 | 119期号:4页码:997-1007 |
英文摘要 | Hedgehog (HH) signaling is activated in various lymphoid malignancies, but conflicting results exist about its role in chronic lymphocytic leukemia (CLL). Here, we demonstrate that the expression of essential HH pathway components like GUI1, PTCH1, and the HH ligands is highly diverse in CLL. A subset of 36.7% of 60 tested CLL samples responded to all 3 SMOOTHENED (SMO) inhibitors, whereas 40% were completely resistant. Responsiveness correlated with elevated GLI1 and PTCH1 transcript levels and the presence of trisomy 12, whereas no other karyotype correlated with responsiveness. All trisomy 12 CLLs displayed constitutive HH pathway activation driven by autocrine DESERT HH (DHH) ligand secretion, which could be blocked by the HH-blocking Ab 5E1. Cocultures with DHH-expressing BM stromal cells reduced sensitivity of CLLs to SMO-inhibitor treatment by activation of noncanonical ERK phosphorylation directly downstream of the PTCH1 receptor without involvement of SMO and could be overcome by the HH-blocking Ab 5E1 or a combination of SMO and ERK inhibitors. Our results demonstrate that the HH-signaling pathway is an interesting therapeutic target for a subset of patients with CLL, characterized by high Oil and PTCH1 transcript levels, and all patients with trisomy 12 and indicate HH-blocking Abs to be favorable over SMO inhibitors in overcoming stroma-mediated protective effects. (Blood. 2012;119(4):997-1007) |
类型 | Article |
语种 | 英语 |
国家 | Germany ; USA ; Netherlands |
收录类别 | SCI-E |
WOS记录号 | WOS:000299860700014 |
WOS关键词 | CHRONIC LYMPHOCYTIC-LEUKEMIA ; BASAL-CELL CARCINOMAS ; GENE MUTATION STATUS ; SONIC HEDGEHOG ; B-CELLS ; SIGNALING PATHWAY ; STEM-CELLS ; SURVIVAL ; CANCER ; ACTIVATION |
WOS类目 | Hematology |
WOS研究方向 | Hematology |
资源类型 | 期刊论文 |
条目标识符 | http://119.78.100.177/qdio/handle/2XILL650/171618 |
作者单位 | 1.Univ Med Ctr Freiburg, Dept Hematol Oncol, D-79106 Freiburg, Germany; 2.Univ Freiburg, Fac Biol, D-79106 Freiburg, Germany; 3.Univ Med Ctr Freiburg, Dept Med Biometry & Stat, Clin Trials Unit, D-79106 Freiburg, Germany; 4.Univ Med Ctr Freiburg, Dept Pathol, D-79106 Freiburg, Germany; 5.H3 Biomed, Cambridge, MA USA; 6.Leiden Univ, Med Ctr, Dept Hematol, Leiden, Netherlands |
推荐引用方式 GB/T 7714 | Decker, Sarah,Zirlik, Katja,Djebatchie, Lauritte,et al. Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL[J],2012,119(4):997-1007. |
APA | Decker, Sarah.,Zirlik, Katja.,Djebatchie, Lauritte.,Hartmann, David.,Ihorst, Gabriele.,...&Dierks, Christine.(2012).Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL.BLOOD,119(4),997-1007. |
MLA | Decker, Sarah,et al."Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL".BLOOD 119.4(2012):997-1007. |
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