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C. Ciardullo et al.
Discussion
Given the central role of p53 in preventing aberrant cell proliferation and maintaining genomic integrity, as well as in the response to chemotherapy, there is increasing inter- est in the development of pharmacological strategies aimed at activating p53.20,21 These strategies include com- pounds that rely on non-genotoxic activation of p53 by
A
preventing it from being inhibited and targeted for degra- dation by MDM2, thus stabilizing p53 and activating its transcriptional activity to promote p53-induced apoptosis.20,21,24,25 Here, we provide a strong rationale for the future evaluation of MDM2 inhibitors in CLL therapy, based on our observations that CLL cells are particularly primed for p53-dependent apoptosis compared with nor- mal PBMC, BMMC and CD34+ hematopoietic stem cells.
C
B
Figure 7. RG7388 preferentially induces MDM2 mRNA in normal peripheral blood mononuclear cells, bone marrow mononuclear cells and CD34+-selected bone mar- row cells from healthy donors. Real-time reverse transcriptase polymerase chain reaction plots for (A) one representative sample of normal peripheral blood mononu- clear cells (PBMC) sample, (B) one representative sample of normal bone marrow mononuclear cells (BMMC) sample and (C) one representative sample of normal CD34+ hematopoietic stem cells (CD34+ cells) all showing preferential induction of MDM2 after treatment with increasing concentrations (0.1, 0.3, 1 and 3 μM) of RG7388 for 6 h and 24 h. Data are presented as mean ± standard error of mean (SEM) of at least three replicates.
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haematologica | 2019; 104(12)