Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia
Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia
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DOI：
10.1182/blood-2018-09-873695
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发表时间：
2019-06-20
期刊：
影响因子：
20.3
通讯作者：
Kipps, Thomas J.
中科院分区：
文献类型：
--
作者：
Ghia, Emanuela M.;Rassenti, Laura Z.;Kipps, Thomas J.
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 (chi(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.
