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

Abstract:

: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 (χ2 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.

journal_name

Blood

journal_title

Blood

authors

Ghia EM,Rassenti LZ,Neuberg DS,Blanco A,Yousif F,Smith EN,McPherson JD,Hudson TJ,HALT Pan-Leukemia Gene Panel Consortium.,Harismendy O,Frazer KA,Kipps TJ

doi

10.1182/blood-2018-09-873695

subject

Has Abstract

pub_date

2019-06-20 00:00:00

pages

2651-2663

issue

25

eissn

0006-4971

issn

1528-0020

pii

blood-2018-09-873695

journal_volume

133

pub_type

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