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Non-genotoxic MDM2 inhibition selectively induces pro-apoptotic p53 gene signature in chronic lymphocytic leukemia cells

Lookup NU author(s): Dr Carmela Ciardullo, Erhan Aptullahoglu, Dr Laura Woodhouse, Dr Wei-Yu Lin, Dr Jonathan Wallis, Dr Helen Marr, Dr Elaine Willmore, Professor John Lunec

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Abstract

Chronic lymphocytic leukemia is a clinically heterogeneous haematological malignancy which is ~90% TP53 wild-type at diagnosis. As a primary repressor of p53, targeting of mouse double-minute-2 homolog (MDM2) is an attractive therapeutic approach for nongenotoxic reactivation of p53. Since discovery of the first MDM2 inhibitor, Nutlin-3a, newer potent and bioavailable compounds have been developed. Here, we tested the secondgeneration MDM2 inhibitor, RG7388, in patient-derived chronic lymphocytic leukemia cells and normal cells, examining its effect on the induction of p53-transcriptional targets. RG7388 potently decreased viability in p53-functional chronic lymphocytic leukemia cells whereas p53-non-functional samples were more drug-resistant. RG7388 induced a pro-apoptotic gene expression signature with upregulation of p53-target genes involved in the intrinsic (PUMA, BAX) and extrinsic (TNFRSF10B, FAS) pathway of apoptosis, as well as MDM2. A slight induction of CDKN1A was observed and upregulation of pro-apoptotic genes dominated, indicating that chronic lymphocytic leukemia cells are primed for p53-dependent apoptosis. Consequently, RG7388 led to a concentration-dependent increase in caspase-3/7 activity and cleaved PARP. Importantly, we observed a preferential pro-apoptotic signature in chronic lymphocytic leukemia cells but not in normal blood and bone marrow cells, including CD34+ haematopoietic cells. These data support the further evaluation of MDM2 inhibitors as a novel additional treatment option for patients with p53-functional chronic lymphocytic leukemia.


Publication metadata

Author(s): Ciardullo C, Aptullahoglu E, Woodhouse L, Lin WY, Wallis JP, Marr H, Marshall S, Bown N, Willmore E, Lunec J

Publication type: Article

Publication status: Published

Journal: Haematologica

Year: 2019

Volume: 104

Pages: ePub ahead of print

Online publication date: 19/04/2019

Acceptance date: 16/04/2019

Date deposited: 27/06/2019

ISSN (print): 0390-6078

ISSN (electronic): 1592-8721

Publisher: Ferrata Storti Foundation

URL: https://doi.org/10.3324/haematol.2018.206631

DOI: 10.3324/haematol.2018.206631

PubMed id: 31004033


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