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

Decker S , Zirlik K , Djebatchie L , Hartmann D , Ihorst G , Schmitt-Graeff A , Herchenbach D , Jumaa H , Warmuth M , Veelken H , Dierks C
Hedgehog (HH) signaling is activated in various lymphoid malignancies, but conflicting results exist regarding 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 SMO-inhibitors, while 40% were completely resistant. Responsiveness correlated with elevated GLI1 and PTCH1 transcript levels and the presence of trisomy 12, while no other karyotype correlated with responsiveness. All trisomy 12 CLLs displayed constitutive HH pathway activation driven by autocrine DHH ligand secretion, which could be blocked by the HH-blocking antibody 5E1. Cocultures with DHH expressing bone marrow stromal cells reduced sensitivity of CLLs to SMO-inhibitor treatment by activation of non-canonical ERK-phosphorylation directly downstream of the PTCH1-receptor without involvement of SMO and could be overcome by the HH-blocking antibody 5E1 or a combination of SMO- and ERK-inhibitors. Our results demonstrate that the HH signaling pathway is an interesting therapeutical target for a subset of CLL patients, characterized by high GLI1 and PTCH1 transcript levels and all trisomy 12 patients and indicates HH-blocking antibodies to be favourable over SMO-inhibitors in overcoming stroma-mediated protective effects.

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