Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia

Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naive patients with chronic lymphocytic leukemia (CLL) identified 89 (11%) patients as having CLL cells with mutations in genes encoding proteins that putatively are involved in hedgehog (Hh) signaling. Consistent with this finding, there was a significant association between the presence of these mutations and the expression of GLI1 (2 test, P < .0001), reflecting activation of the Hh pathway. However, we discovered that 38% of cases without identified mutations also were GLI1+. Patients with GLI1+ CLL cells had a shorter median treatment-free survival than patients with CLL cells lacking expression of GLI1 independent of IGHV mutation status. We found that GANT61, a small molecule that can inhibit GLI1, was highly cytotoxic for GLI1+ CLL cells relative to that of CLL cells without GLI1. Collectively, this study shows that a large proportion of patients have CLL cells with activated Hh signaling, which is associated with early disease progression and enhanced sensitivity to inhibition of GLI1.

Source: Blood - June 19, 2019 Category: Hematology Authors: Ghia, E. M., Rassenti, L. Z., Neuberg, D. S., Blanco, A., Yousif, F., Smith, E. N., McPherson, J. D., Hudson, T. J., the HALT Pan-Leukemia Gene Panel Consortium, Harismendy, O., Frazer, K. A., Kipps, T. J. Tags: Lymphoid Neoplasia Source Type: research