학술논문
Non-genotoxic MDM2 inhibition selectively induces a pro-apoptotic p53 gene signature in chronic lymphocytic leukemia cells.
Document Type
Academic Journal
Author
Ciardullo C; Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne.; Aptullahoglu E; Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne.; Woodhouse L; Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne.; Lin WY; Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne.; Wallis JP; Department of Haematology, Freeman Hospital, The Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne.; Marr H; Department of Haematology, Freeman Hospital, The Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne.; Marshall S; Department of Haematology, City Hospitals Sunderland NHS Trust, Sunderland.; Bown N; Northern Genetics Service, Institute of Genetic Medicine, Newcastle upon Tyne, UK.; Willmore E; Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne.; Lunec J; Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne john.lunec@ncl.ac.uk.
Source
Publisher: Ferrata Storti Foundation Country of Publication: Italy NLM ID: 0417435 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1592-8721 (Electronic) Linking ISSN: 03906078 NLM ISO Abbreviation: Haematologica Subsets: MEDLINE
Subject
Language
English
Abstract
Chronic lymphocytic leukemia (CLL) is a clinically heterogeneous hematologic malignancy. In approximately 90% of cases the TP53 gene is in its wildtype state at diagnosis of this malignancy. As mouse double-minute-2 homolog (MDM2) is a primary repressor of p53, targeting this protein is an attractive therapeutic approach for non-genotoxic reactivation of p53. Since the discovery of the first MDM2 inhibitor, Nutlin-3a, newer potent and bioavailable compounds have been developed. In this study we tested the second-generation MDM2 inhibitor, RG7388, in patient-derived CLL cells and normal cells, examining its effect on the induction of p53-transcriptional targets. RG7388 potently decreased viability in p53-functional CLL cells, whereas p53-non-functional samples were more resistant to the drug. RG7388 induced a pro-apoptotic gene expression signature with upregulation of p53-target genes involved in the intrinsic ( PUMA , BAX ) and extrinsic ( TNFRSF10B , FAS ) pathways of apoptosis, as well as MDM2 Only a slight induction of CDKN1A was observed and upregulation of pro-apoptotic genes dominated, indicating that CLL cells are primed for p53-dependent apoptosis. Consequently, RG7388 led to a concentration-dependent increase in caspase-3/7 activity and cleaved poly (ADP-ribose) polymerase. Importantly, we observed a preferential pro-apoptotic signature in CLL cells but not in normal blood and bone marrow cells, including CD34 + hematopoietic cells. These data support the further evaluation of MDM2 inhibitors as a novel additional treatment option for patients with p53-functional CLL.
(Copyright© 2019 Ferrata Storti Foundation.)
(Copyright© 2019 Ferrata Storti Foundation.)