Arid
DOI10.1182/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
ISSN0006-4971
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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