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

Emanuela M. Ghia, Laura Z. Rassenti, Donna S. Neuberg, Alejandro Blanco, Fouad Yousif, Erin N. Smith, John D. McPherson, Thomas J. Hudson, Olivier Harismendy, Kelly A. Frazer and Thomas J. Kipps

Key points

  • A large proportion of patients have CLL cells with activation of Hh-signaling leading to expression of GLI1.

  • Activation of Hh signaling predicts for relatively short TFS and sensitivity to GLI1 inhibition.


Targeted sequencing of 103 leukemia-associated genes in leukemia cells from 841 treatment-naïve patients with chronic lymphocytic leukemia (CLL) identified 89 (11%) patients have CLL cells with mutations in genes encoding proteins that putatively are involved in Hedgehog (Hh) signaling. Consistent with this, we found that there was a significant association between the presence of these mutations and the expression of GLI1 (Chi square test P < 0.0001), 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 (TFS) 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.

  • Submitted September 5, 2018.
  • Accepted March 11, 2019.