Activation of hedgehog signaling associates with early disease progression in chronic lymphocytic leukemia
| Autor: | Kelly A. Frazer, John Douglas Mcpherson, Thomas J. Hudson, Emanuela M. Ghia, Laura Z. Rassenti, Erin N. Smith, Donna Neuberg, Fouad Yousif, Alejandro Toro Blanco, Olivier Harismendy, Thomas J. Kipps |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Adult
Male 0301 basic medicine Pyridines Chronic lymphocytic leukemia Immunology medicine.disease_cause Biochemistry Zinc Finger Protein GLI1 03 medical and health sciences 0302 clinical medicine GLI1 immune system diseases hemic and lymphatic diseases Cytotoxic T cell Medicine Humans Hedgehog Proteins Hedgehog Aged Aged 80 and over Mutation Lymphoid Neoplasia biology integumentary system Gene Expression Regulation Leukemic business.industry Cell Biology Hematology Middle Aged medicine.disease Leukemia Lymphocytic Chronic B-Cell Hedgehog signaling pathway Leukemia Pyrimidines 030104 developmental biology 030220 oncology & carcinogenesis Cancer research biology.protein Disease Progression Female IGHV@ business Signal Transduction |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|