Activation of Hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia.
Ghia EM , Rassenti LZ , Neuberg DS , Blanco A , Yousif F , Smith EN , McPherson JD , Hudson TJ , Harismendy O , Frazer KA , Kipps TJ
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.
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