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Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia.
- Source :
-
Blood [Blood] 2019 Jun 20; Vol. 133 (25), pp. 2651-2663. Date of Electronic Publication: 2019 Mar 28. - Publication Year :
- 2019
-
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 (χ <superscript>2</superscript> test, P < .0001), reflecting activation of the Hh pathway. However, we discovered that 38% of cases without identified mutations also were GLI1 <superscript>+</superscript> Patients with GLI1 <superscript>+</superscript> 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 <superscript>+</superscript> 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.<br /> (© 2019 by The American Society of Hematology.)
- Subjects :
- Adult
Aged
Aged, 80 and over
Disease Progression
Female
Gene Expression Regulation, Leukemic genetics
Humans
Leukemia, Lymphocytic, Chronic, B-Cell genetics
Leukemia, Lymphocytic, Chronic, B-Cell metabolism
Male
Middle Aged
Pyridines pharmacology
Pyrimidines pharmacology
Signal Transduction drug effects
Signal Transduction physiology
Hedgehog Proteins metabolism
Leukemia, Lymphocytic, Chronic, B-Cell pathology
Zinc Finger Protein GLI1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 133
- Issue :
- 25
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 30923040
- Full Text :
- https://doi.org/10.1182/blood-2018-09-873695