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Haematologica. 2019 Apr 19. pii: haematol.2018.206631. doi: 10.3324/haematol.2018.206631. [Epub ahead of print]

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

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Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK.
Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
Dept Haematology, Freeman Hospital,Newcastle upon Tyne NHS Foundation Trust, Newcastle upon Tyne, UK.
Department of Haematology, City Hospitals Sunderland NHS Trust, Sunderland, UK.
Northern Genetics Service, Institute of Genetic Medicine, Newcastle upon Tyne, UK.
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK;


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 non-genotoxic reactivation of p53. Since discovery of the first MDM2 inhibitor, Nutlin-3a, newer potent and bioavailable compounds have been developed. Here, we tested the second-generation 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.


Chronic Lymphocytic Leukemia; Lymphocytes; Lymphoproliferative Disorders; Molecular Pharmacology

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