NDLI: Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL

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Trisomy 12 and elevated GLI1 and PTCH1 transcript levels are biomarkers for Hedgehog-inhibitor responsiveness in CLL

Content Provider	Scilit
Author	Decker, Sarah Zirlik, Katja Djebatchie, Lauritte Hartmann, David Ihorst, Gabriele Schmitt-Graeff, Annette Herchenbach, Dieter Jumaa, Hassan Warmuth, Markus Veelken, Hendrik Dierks, Christine
Copyright Year	2012
Description	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 GLI1, 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 GLI1 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.
Related Links	http://www.bloodjournal.org/content/119/4/997.full.pdf
DOI	10.1182/blood-2011-06-359075
Journal	Blood
Issue Number	4
Volume Number	119
Language	English
Publisher	American Society of Hematology
Publisher Date	2012-01-26
Access Restriction	Open
Subject Keyword	Hematology Research and Experimental Medicine Cll Ptch1 Signaling Inhibitors Smo Inhibitor Elevated Gli1 Phosphorylation Trisomy Journal: Blood (Vol- 79, Issue- 4)
Content Type	Text
Resource Type	Article

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